Compounds as opioid receptor modulators

ABSTRACT

The present invention is directed to novel opioid receptor modulators of Formula (I). 
     
       
         
         
             
             
         
       
     
     The invention further relates to methods for preparing such compounds, pharmaceutical compositions containing them, and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. Ser. No. 12/838,825,filed Jul. 19, 2010 (now U.S. Pat. No. 8,344,011), which is a divisionalof U.S. Ser. No. 11/877,747, filed Oct. 24, 2007 (now U.S. Pat. No.7,786,158), which is a continuation of U.S. Ser. No. 11/079,647, filedMar. 14, 2005 (now U.S. Pat. No. 7,741,356), which claims the benefit ofU.S. Provisional App. No. 60/553,342, filed Mar. 15, 2004, the entirecontents of each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention is directed to novel opioid receptor modulators ofFormula (I). The invention further relates to methods for preparing suchcompounds, pharmaceutical compositions containing them, and their use inthe treatment of opioid modulated disorders.

BACKGROUND OF THE INVENTION

The opioid receptors were identified in the mid-1970's, and were quicklycategorized into three sub-sets of receptors (mu, delta and kappa). Morerecently the original three types of receptors have been further dividedinto sub-types. Also known is that the family of opioid receptors aremembers of the G-protein coupled receptor (GPCR) super-family. Morephysiologically pertinent are the well established facts that opioidreceptors are found throughout the central and peripheral nervous systemof many mammalian species, including humans, and that modulation of therespective receptors can elicit numerous, albeit different, biologicaleffects, both desirable and undesirable (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, andD. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp.247-269; J. V. Aldrich, “Analgesics”, Burger's Medicinal Chemistry andDrug Discovery, 5^(th) Edition, Volume 3: Therapeutic Agents, John Wiley& Sons, Inc., 1996, pp. 321-441). In the most current literature, thelikelihood of heterodimerization of the sub-classes of opioid receptorshas been reported, with respective physiological responses yetundetermined (Pierre J. M. Riviere and Jean-Louis Junien, “Opioidreceptors: Targets for new gastrointestinal drug development”, DrugDevelopment 2000, pp. 203-238).

A couple biological effects identified for opioid modulators have led tomany useful medicinal agents. Most significant are the many centrallyacting mu opioid agonist modulators marketed as analgesic agents toattenuate pain (e.g., morphine), as well as peripherally acting muagonists to regulate motility (e.g., loperamide). Currently, clinicalstudies are continuing to evaluate medicinal utility of selective delta,mu, and kappa modulators, as well as compounds possessing combinedsub-type modulation. It is envisioned such explorations may lead toagents with new utilities, or agents with minimized adverse side effectsrelative to currently available agents (examples of side effects formorphine includes constipation, respiratory depression, and addictionpotential). Some new GI areas where selective or mixed opioid modulatorsare currently being evaluated includes potential treatment for variousdiarrheic syndromes, motility disorders (post-operative ileus,constipation), and visceral pain (post operative pain, irritable bowelsyndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere andJean-Louis Junien, “Opioid receptors: Targets for new gastrointestinaldrug development” Drug Development, 2000, pp. 203-238).

Around the same time the opioid receptors were identified, theenkephalins were identified as a set of endogenous opioid ligands (D. S.Fries, “Analgesics”, in Principles of Medicinal Chemistry, 4th ed.; W.O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins:Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncatingthe original pentapeptide enkephalins to simplified dipeptides yielded aseries of compounds that maintained opioid activity (Schiller, P. WO96/06855). However one potential drawback cited for such compounds isthe likelihood of their inherent instability (P. W. Schiller et al.,Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

More recently, a series of opioid pseudopeptides containingheteroaromatic or heteroaliphatic nuclei were disclosed, however thisseries is reported showing a different functional profile than thatdescribed in the Schiller works. (L. H. Lazarus et al., Peptides 2000,21, pp. 1663-1671)

Most recently, works around morphine related structures were reported byWentland, et al, where carboxamido morphine derivatives and it's analogswere prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001,11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters2001, 11, pp. 623-626). Wentland found that substitution for the phenolmoiety of the morphine related structures with a primary carboxamide ledanywhere from equal activities up to 40 fold reduced activities,depending on the opioid receptor and the carboxamide. It was alsorevealed that any additional N-substitutions on the carboxamidesignificantly diminished the desired binding activity.

Compounds of the present invention have not been previously disclosedand are believed to provide advantages over related compounds byproviding improved pharmacological profiles.

Opioid receptor modulators, agonists or antagonists are useful in thetreatment and prevention of various mammalian disease states, forexample pain and gastrointestinal disorders such as diarrheic syndromes,motility disorders including post-operative ileus and constipation, andvisceral pain including post-operative pain, irritable bowel syndromeand inflammatory bowel disorders.

It is an object of the present invention to provide opioid receptormodulators. It is a further object of the invention to provide opioidreceptor agonists and opioid receptor antagonists. It is an object ofthe present invention to provide opioid receptor ligands that areselective for each type of opioid receptor, mu, delta and kappa. It is afurther object of the present invention to provide opioid receptorligands that modulate two or three opioid receptor types, mu, delta andkappa, simultaneously. It is an object of the invention to providecertain instant compounds that are also useful as intermediates inpreparing new opioid receptor modulators. It is also an object of theinvention to provide a method of treating or ameliorating a conditionmediated by an opioid receptor. And, it is an object of the invention toprovide a useful pharmaceutical composition comprising a compound of thepresent invention useful as an opioid receptor modulator.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula (I)

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl,        cycloalkyl, heterocyclyl, aryl(C₁₋₆)alkyl, and        heteroaryl(C₁₋₆)alkyl; wherein aryl of aryl(C₁₋₆)alkyl is        optionally fused to a heterocyclyl or cycloalkyl;    -   and wherein the cycloalkyl and heterocyclyl of R¹ are optionally        substituted with C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy,        hydroxy, cyano, amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino,        halogen, carboxy, aryl(C₁₋₆)alkoxycarbonyl, C₁₋₆alkoxycarbonyl,        aminocarbonyl, C₁₋₆alkylaminocarbonyl,        (C₁₋₆alkyl)₂aminocarbonyl, or aminosulfonyl;    -   and, wherein C₁₋₆alkyl of R¹ is optionally substituted with one        to three substituents independently selected from the group        consisting of C₁₋₆alkoxy, aryl, cycloalkyl, heterocyclyl,        hydroxy, cyano, amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino,        halogen, and carboxy;    -   and wherein the aryl and heteroaryl portion of aryl(C₁₋₆)alkyl        and heteroaryl(C₁₋₆)alkyl are optionally substituted with one to        three R¹¹ substituents independently selected from the group        consisting of C₁₋₆alkyl; hydroxy(C₁₋₆)alkyl; C₁₋₆alkoxy;        aryl(C₁₋₆)alkyl; aryl(C₁₋₆)alkoxy; aryl; heteroaryl optionally        substituted with C₁₋₄alkyl; cycloalkyl; heterocyclyl; aryloxy;        heteroaryloxy; cycloalkyloxy; heterocyclyloxy; amino;        C₁₋₆alkylamino; (C₁₋₆alkyl)₂amino; C₃₋₆cycloalkylaminocarbonyl;        hydroxy(C₁₋₆)alkylaminocarbonyl; arylaminocarbonyl wherein aryl        is optionally substituted with carboxy or C₁₋₄alkoxycarbonyl;        heterocyclylcarbonyl; carboxy; C₁₋₆alkoxycarbonyl;        C₁₋₆alkylcarbonyl; C₁₋₆alkylcarbonylamino; aminocarbonyl;        C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl; cyano;        halogen; trifluoromethyl; trifluoromethoxy; or hydroxy;    -   R² is selected from the group consisting of hydrogen, C₁₋₈alkyl,        hydroxy(C₁₋₈)alkyl, aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl, or        aryl(C₁₋₈)alkyl;        -   wherein the aryl portion of the aryl-containing substituents            of R² are optionally substituted with one to two            substituents independently selected from the group            consisting of C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, amino,            C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, aminocarbonyl,            C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl, cyano,            fluoro, chloro, bromo, trifluoromethyl, and            trifluoromethoxy; and wherein alkyl and alkoxy substituents            of aryl are optionally substituted with hydroxy, amino,            C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, or aryl;    -   A is selected from the group consisting of aryl, ring system        a-1, a-2, a-3, and a-4, optionally substituted with R³ and R⁵;

-   -   -   wherein        -   A-B is selected from the group consisting of N—C, C—N, N—N            and C—C;        -   D-E is selected from the group consisting of O—C, S—C, and            O—N;

    -   R³ is one to two substituents independently selected from the        group consisting of C₁₋₆alkyl, aryl, aryl(C₁₋₆)alkyl,        aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, heteroaryl,        heteroaryl(C₁₋₆)alkyl, heteroaryl(C₂₋₆)alkenyl,        heteroaryl(C₂₋₆)alkynyl, amino, C₁₋₆alkylamino,        (C₁₋₆alkyl)₂amino, arylamino, heteroarylamino, aryloxy,        heteroaryloxy, and halogen;

    -   wherein the aryl and heteroaryl portion of R³ are optionally        substituted with one to five substituents independently selected        from the group consisting of C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl,        C₁₋₆alkoxy, aryl(C₁₋₆)alkyl, aryl(C₁₋₆)alkoxy, aryl, aryloxy,        heteroaryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkoxy, heteroaryl,        heteroaryloxy, arylamino, heteroarylamino, amino,        C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, carboxy(C₁₋₆)alkylamino,        carboxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,        C₁₋₆alkylcarbonylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl,        (C₁₋₆alkyl)₂aminocarbonyl, carboxy(C₁₋₆)alkylaminocarbonyl,        cyano, halogen, trifluoromethyl, trifluoromethoxy, hydroxy,        C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonylamino,        —C(O)—NH—CH(—R^(c))—C(O)—NH₂, and C₁₋₆alkyl;

    -   wherein C₁₋₆alkyl of R³ is optionally substituted with a        substituent selected from the group consisting of hydroxy,        carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₆alkylamino,        (C₁₋₆alkyl)₂amino, aminocarbonyl, (C₁₋₄)alkylaminocarbonyl,        di(C₁₋₄)alkylaminocarbonyl, aryl, heteroaryl, arylamino,        heteroarylamino, aryloxy, heteroaryloxy, aryl(C₁₋₄)alkoxy, and        heteroaryl(C₁₋₄)alkoxy;

    -   R^(c) is selected from the group consisting of hydrogen,        C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,        C₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl,        aryl, and heteroaryl;

    -   R⁴ is aryl or heteroaryl; wherein R⁴ is optionally substituted        with one to five substituents independently selected from the        group R⁴¹; wherein R⁴¹ is (C₁₋₆)alkyl, (C₁₋₆)alkoxy,        aryl(C₁₋₆)alkoxy, aryl(C₁₋₆)alkylcarbonyloxy,        heteroaryl(C₁₋₆)alkylcarbonyloxy, heteroaryl, hydroxy, halogen,        aminosulfonyl, formylamino, aminocarbonyl,        C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl,        heterocyclylcarbonyl, carboxy, or cyano; and wherein C₁₋₆alkyl        is optionally substituted with amino, C₁₋₆alkylamino, or        (C₁₋₆alkyl)₂amino; and wherein the aryl portion of        aryl(C₁₋₆)alkylcarbonyloxy is optionally substituted with one to        four substituents independently selected from the group        consisting of (C₁₋₆)alkyl, (C₁₋₆)alkoxy, halogen, cyano, amino,        and hydroxy;

    -   R⁵ is a substituent on a nitrogen atom contained in ring A        selected from the group consisting of hydrogen, C₁₋₄alkyl, and        aryl;

    -   R⁶ is selected from the group consisting of hydrogen and        C₁₋₆alkyl;

    -   R⁷ is selected from the group consisting of hydrogen and        C₁₋₆alkyl;

    -   R^(a) and R^(b) are substituents independently selected from the        group consisting of hydrogen and C₁₋₆alkyl; or, when R^(a) and        R^(b) are other than hydrogen, R^(a) and R^(b) are optionally        taken together with the nitrogen to which they are both attached        to form a five to eight membered monocyclic ring;

    -   L is selected from the group consisting of O, S, and N(R^(d));        wherein R^(d) is hydrogen, C₁₋₆alkyl, or aryl;

    -   and pharmaceutically acceptable enantiomers, diastereomers,        racemates, and salts thereof.

The present invention is also directed to compounds of Formula (I)

-   -   wherein:        -   R¹ is selected from the group consisting of hydrogen,            C₁₋₆alkyl, cycloalkyl, heterocyclyl, aryl(C₁₋₆)alkyl, and            heteroaryl(C₁₋₆)alkyl; wherein when R¹ is phenyl(C₁₋₆)alkyl,            phenyl is optionally fused to a heterocyclyl or cycloalkyl;        -   wherein when R¹ is C₁₋₂alkyl, said C₁₋₂alkyl is optionally            substituted with one to two substituents independently            selected from the group consisting of C₁₋₆alkoxy, aryl,            cycloalkyl, heterocyclyl, hydroxy, cyano, amino,            C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, trifluoromethyl, and            carboxy;        -   and further, wherein when R¹ is C₃₋₆alkyl, said C₃₋₆alkyl is            optionally substituted with one to three substituents            independently selected from the group consisting of            C₁₋₆alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy, cyano,            amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, trifluoromethyl,            and carboxy;            -   wherein the cycloalkyl and heterocyclyl of C₁₋₂alkyl and                C₃₋₆alkyl are optionally substituted with one to two                substituents independently selected from the group                consisting of C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy,                hydroxy, cyano, amino, C₁₋₆alkylamino,                (C₁₋₆alkyl)₂amino, trifluoromethyl, carboxy,                aryl(C₁₋₆)alkoxycarbonyl, C₁₋₆alkoxycarbonyl,                aminocarbonyl, C₁₋₆alkylaminocarbonyl,                (C₁₋₆alkyl)₂aminocarbonyl, and aminosulfonyl;        -   furthermore, wherein the cycloalkyl and heterocyclyl of R¹            are optionally substituted with one to two substituents            independently selected from the group consisting of            C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy, hydroxy, cyano,            amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, trifluoromethyl,            carboxy, aryl(C₁₋₆)alkoxycarbonyl, C₁₋₆alkoxycarbonyl,            aminocarbonyl, C₁₋₆alkylaminocarbonyl,            (C₁₋₆alkyl)₂aminocarbonyl, and aminosulfonyl;        -   furthermore, wherein the aryl and heteroaryl portion of the            R¹ substituents aryl(C₁₋₆)alkyl and heteroaryl(C₁₋₆)alkyl,            are optionally substituted with one to three R¹¹            substituents independently selected from the group            consisting of C₁₋₆alkyl; hydroxy(C₁₋₆)alkyl; C₁₋₆alkoxy;            C₆₋₁₀aryl(C₁₋₆)alkyl; C₆₋₁₀aryl(C₁₋₆)alkoxy; C₆₋₁₀aryl;            heteroaryl optionally substituted with one to two            substituents independently selected from the group            consisting of C₁₋₄alkyl, C₁₋₄alkoxy, and carboxy;            cycloalkyl; heterocyclyl; C₆₋₁₀aryloxy; heteroaryloxy;            cycloalkyloxy; heterocyclyloxy; amino; C₁₋₆alkylamino;            (C₁₋₆alkyl)₂amino; C₃₋₆cycloalkylaminocarbonyl;            hydroxy(C₁₋₆)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl            wherein C₆₋₁₀aryl is optionally substituted with carboxy or            C₁₋₄alkoxycarbonyl; heterocyclylcarbonyl; carboxy;            C₁₋₆alkylcarbonyloxy; C₁₋₆alkoxycarbonyl; C₁₋₆alkylcarbonyl;            C₁₋₆alkylcarbonylamino; aminocarbonyl;            C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl; cyano;            halogen; trifluoromethyl; trifluoromethoxy; and hydroxy;        -   provided that no more than one R¹¹ substituent is selected            from the group consisting of C₆₋₁₀aryl(C₁₋₆)alkyl;            C₆₋₁₀aryl(C₁₋₆)alkoxy; C₆₋₁₀aryl; heteroaryl optionally            substituted with one to two substituents independently            selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,            and carboxy; cycloalkyl; heterocyclyl; C₆₋₁₀aryloxy;            heteroaryloxy; cycloalkyloxy; C₆₋₁₀arylaminocarbonyl,            heterocyclylcarbonyl; and heterocyclyloxy;    -   R² is hydrogen, C₁₋₈alkyl, hydroxy(C₁₋₈)alkyl,        C₆₋₁₀aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl, or C₆₋₁₀aryl(C₁₋₈)alkyl;        -   wherein the C₆₋₁₀aryl group in the C₆₋₁₀aryl-containing            substituents of R² are optionally substituted with one to            two substituents independently selected from the group            consisting of C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, amino,            C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, aminocarbonyl,            C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl, cyano,            fluoro, chloro, bromo, trifluoromethyl, and            trifluoromethoxy; and, wherein the C₁₋₆alkyl and C₁₋₆alkoxy            substituents of aryl are optionally substituted with            hydroxy, amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, or C₁₋₆            aryl;    -   A is selected from the group consisting of aryl, ring system        a-1, a-2, a-3, and a-4, optionally substituted with R³ and R⁵;

-   -   -   wherein        -   A-B is selected from the group consisting of N—C, C—N, N—N            and C—C;        -   D-E is selected from the group consisting of O—C, S—C, and            O—N;        -   F-G is selected from the group consisting of N—O and C—O;

    -   R³ is one to two substituents independently selected from the        group consisting of C₁₋₆alkyl, aryl, aryl(C₁₋₆)alkyl,        aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, heteroaryl,        heteroaryl(C₁₋₆)alkyl, heteroaryl(C₂₋₆)alkenyl,        heteroaryl(C₂₋₆)alkynyl, amino, C₁₋₆alkylamino,        (C₁₋₆alkyl)₂amino, arylamino, heteroarylamino, aryloxy,        heteroaryloxy, trifluoromethyl, and halogen;        -   wherein the aryl,heteroaryl and the aryl and heteroaryl of            aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl,            heteroaryl(C₁₋₆)alkyl, heteroaryl(C₂₋₆)alkenyl,            heteroaryl(C₂₋₆)alkynyl, arylamino, heteroarylamino,            aryloxy, and heteroaryloxy, are optionally substituted with            one to five fluoro substituents or one to three substituents            independently selected from the group consisting of            C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy,            C₆₋₁₀aryl(C₁₋₆)alkyl, C₆₋₁₀aryl(C₁₋₆)alkoxy, C₆₋₁₀aryl,            C₆₋₁₀aryloxy, heteroaryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkoxy,            heteroaryl, heteroaryloxy, C₆₋₁₀arylamino, heteroarylamino,            amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino,            carboxy(C₁₋₆)alkylamino, carboxy, C₁₋₆alkylcarbonyl,            C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, aminocarbonyl,            C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl,            carboxy(C₁₋₆)alkylaminocarbonyl, cyano, halogen,            trifluoromethyl, trifluoromethoxy, hydroxy,            C₁₋₆alkylsulfonyl, and C₁₋₆alkylsulfonylamino; provided that            no more than one such substituent on the aryl or heteroaryl            portion of R³ is selected from the group consisting of            C₆₋₁₀aryl(C₁₋₆)alkyl, C₆₋₁₀aryl(C₁₋₆)alkoxy, C₆₋₁₀aryl,            C₆₋₁₀aryloxy, heteroaryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkoxy,            heteroaryl, heteroaryloxy, C₆₋₁₀arylamino, and            heteroarylamino;        -   and wherein C₁₋₆alkyl, and C₁₋₆alkyl of aryl(C₁₋₆)alkyl and            heteroaryl(C₁₋₆)alkyl is optionally substituted with a            substituent selected from the group consisting of hydroxy,            carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₆alkylamino,            (C₁₋₆alkyl)₂amino, aminocarbonyl, (C₁₋₄)alkylaminocarbonyl,            di(C₁₋₄)alkylaminocarbonyl, aryl, heteroaryl, arylamino,            heteroarylamino, aryloxy, heteroaryloxy, aryl(C₁₋₄)alkoxy,            and heteroaryl(C₁₋₄)alkoxy;

    -   R⁴ is C₆₋₁₀aryl or a heteroaryl selected from the group        consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,        imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,        indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,        benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl,        quinolinyl, isoquinolinyl and quinazolinyl;        -   wherein R⁴ is optionally substituted with one to three R⁴¹            substituents independently selected from the group            consisting of (C₁₋₆)alkyl optionally substituted with amino,            C₁₋₆alkylamino, or (C₁₋₆alkyl)₂amino; (C₁₋₆)alkoxy;            phenyl(C₁₋₆)alkoxy; phenyl(C₁₋₆)alkylcarbonyloxy wherein the            C₁₋₆ alkyl is optionally substituted with amino; a non fused            5-membered-heteroaryl(C₁₋₆)alkylcarbonyloxy; a non fused            5-membered-heteroaryl; hydroxy; halogen; aminosulfonyl;            formylamino; aminocarbonyl; C₁₋₆alkylaminocarbonyl wherein            C₁₋₆alkyl is optionally substituted with amino,            C₁₋₆alkylamino, or (C₁₋₆alkyl)₂amino;            (C₁₋₆alkyl)₂aminocarbonyl wherein each C₁₋₆alkyl is            optionally substituted with amino, C₁₋₆alkylamino, or            (C₁₋₆alkyl)₂amino; heterocyclylcarbonyl wherein heterocyclyl            is a 5-7 membered nitrogen-containing ring and said            heterocyclyl is attached to the carbonyl carbon via a            nitrogen atom; carboxy; or cyano; and wherein the phenyl            portion of phenyl(C₁₋₆)alkylcarbonyloxy is optionally            substituted with (C₁₋₆)alkyl (C₁₋₆)alkoxy, halogen, cyano,            amino, or hydroxy;        -   provided that no more than one R⁴¹ is (C₁₋₆)alkyl            substituted with C₁₋₆alkylamino or (C₁₋₆alkyl)₂amino;            aminosulfonyl; formylamino; aminocarbonyl;            C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl;            heterocyclylcarbonyl; hydroxy; carboxy; or a phenyl- or            heteroaryl-containing substituent;

    -   R⁵ is a substituent on a nitrogen atom of ring A selected from        the group consisting of hydrogen and C₁₋₄alkyl;

    -   R⁶ is hydrogen or C₁₋₆alkyl;

    -   R⁷ is hydrogen or C₁₋₆alkyl;

    -   R^(a) and R^(b) are independently selected from the group        consisting of hydrogen, C₁₋₆alkyl, and C₁₋₆alkoxycarbonyl;        alternatively, when R^(a) and R^(b) are each other than        hydrogen, R^(a) and R^(b) are optionally taken together with the        nitrogen atom to which they are both attached to form a five to        eight membered monocyclic ring;

    -   L is selected from the group consisting of O, S, and N(R^(d))        wherein R^(d) is hydrogen or C₁₋₆alkyl;

    -   and pharmaceutically acceptable enantiomers, diastereomers,        racemates, and salts thereof.

Illustrative of the invention is a pharmaceutically acceptable carrierand any of the compounds described above.

The present invention is also directed to methods for producing theinstant compounds of Formula (I) and pharmaceutical compositions andmedicaments thereof.

The present invention is further directed to methods for treating opioidmodulated disorders such as pain and gastrointestinal disorders.Compounds of the present invention are believed to provide advantagesover related compounds by providing improved pharmacological profiles.Further specific embodiments of preferred compounds are providedhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic of the protocol to determine visceralhyperalgesia in rats.

FIG. 2 and FIG. 3 each show the effect in rat of Cpd 18 on thehyperalgesic response to colorectal balloon distention followingzymosan.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention include those compounds wherein R¹is selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl(C₁₋₄)alkyl, and heteroaryl(C₁₋₄)alkyl;

-   -   wherein the aryl and heteroaryl portion of aryl(C₁₋₄)alkyl and        heteroaryl(C₁₋₄)alkyl are optionally substituted with one to        three R¹¹ substituents independently selected from the group        consisting of C₁₋₆alkoxy; heteroaryl optionally substituted with        one to two substituents independently selected from the group        consisting of C₁₋₄alkyl, C₁₋₄alkoxy, and carboxy; carboxy;        C₁₋₄alkoxycarbonyl; C₁₋₄alkoxycarbonyloxy; aminocarbonyl;        C₁₋₄alkylaminocarbonyl; C₃₋₆cycloalkylaminocarbonyl;        hydroxy(C₁₋₆)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl wherein        C₆₋₁₀aryl is optionally substituted with carboxy or        C₁₋₄alkoxycarbonyl; heterocyclylcarbonyl; cyano; halogen;        trifluoromethoxy; or hydroxy; provided that no more than one R¹¹        is heteroaryl (optionally substituted with one to two C₁₋₄alkyl        substituents); C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is        optionally substituted with carboxy or C₁₋₄alkoxycarbonyl; or        heterocyclylcarbonyl.

Embodiments of the present invention include those compounds wherein R¹is selected from the group consisting of C₆₋₁₀aryl(C₁₋₄)alkyl,pyridinyl(C₁₋₄)alkyl, and furanyl(C₁₋₄)alkyl; wherein C₆₋₁₀aryl,pyridinyl, and furanyl are optionally substituted with one to three R¹¹substituents independently selected from the group consisting ofC₁₋₃alkoxy; tetrazolyl; carboxy; C₁₋₄alkoxycarbonyl; aminocarbonyl;C₁₋₄alkylaminocarbonyl; C₃₋₆cycloalkylaminocarbonyl;hydroxy(C₁₋₄)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl whereinC₆₋₁₀aryl is optionally substituted with carboxy or C₁₋₄alkoxycarbonyl;morpholin-4-ylcarbonyl; cyano; halogen; and trifluoromethoxy; providedthat that no more than one R¹¹ is C₆₋₁₀arylaminocarbonyl.

Embodiments of the present invention include those compounds wherein R¹is selected from the group consisting of phenyl(C₁₋₃)alkyl,pyridinyl(C₁₋₃)alkyl, and furanyl(C₁₋₃)alkyl; wherein phenyl, pyridinyl,and furanyl are optionally substituted with one to three R¹¹substituents independently selected from the group consisting ofC₁₋₃alkoxy; tetrazolyl, C₃₋₆cycloalkylaminocarbonyl;hydroxy(C₁₋₄)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl whereinC₆₋₁₀aryl is optionally substituted with carboxy or C₁₋₄alkoxycarbonyl;morpholin-4-ylcarbonyl; chloro; fluoro; trifluoromethoxy;C₁₋₄alkoxycarbonyl; and carboxy; provided that that no more than one R¹¹is C₆₋₁₀arylaminocarbonyl.

Embodiments of the present invention include those compounds wherein R¹is phenylmethyl, pyridinylmethyl, or furanylmethyl; wherein phenyl,pyridinyl, and furanyl are optionally substituted with one to three R¹¹substituents independently selected from the group consisting ofmethoxy; tetrazolyl; cyclopropylaminocarbonyl;(2-hydroxyeth-1-yl)aminocarbonyl; methoxycarbonyl; phenylaminocarbonylwherein phenyl is optionally substituted with carboxy;morpholin-4-ylcarbonyl; and carboxy; provided that that no more than oneR¹¹ is phenylaminocarbonyl.

Embodiments of the present invention include those compounds wherein R²is a substituent selected from the group consisting of hydrogen,C₁₋₄alkyl, hydroxy(C₁₋₄)alkyl, and phenyl(C₁₋₆)alkoxy(C₁₋₄)alkyl;

wherein said phenyl is optionally substituted with one to twosubstituents independently selected from the group consisting ofC₁₋₃alkyl, C₁₋₃alkoxy, hydroxy, cyano, fluoro, chloro, bromo,trifluoromethyl, and trifluoromethoxy.

Embodiments of the present invention include those compounds wherein R²is selected from the group consisting of hydrogen and C₁₋₄alkyl.

Embodiments of the present invention include those compounds wherein R²is hydrogen or methyl.

Embodiments of the present invention include those compounds whereinring A is a-1.

Embodiments of the present invention include those compounds wherein A-Bof ring a-1 is selected from the group consisting of N—C and O—N.

Embodiments of the present invention include those compounds wherein A-Bof ring a-1 is N—C.

Embodiments of the present invention include those compounds wherein R³is one to two substituents independently selected from the groupconsisting of C₁₋₆alkyl, halogen, and aryl; wherein aryl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, carboxy, aminocarbonyl,C₁₋₃alkylsulfonylamino, cyano, hydroxy, amino, C₁₋₃alkylamino, and(C₁₋₃alkyl)₂amino.

Embodiments of the present invention include those compounds wherein R³is one to two substituents independently selected from the groupconsisting of C₁₋₃alkyl, bromo, and phenyl; wherein phenyl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of chloro, fluoro, iodo, carboxy, aminocarbonyl,and cyano.

Embodiments of the present invention include those compounds wherein R³is one to two substituents independently selected from the groupconsisting of methyl and phenyl; wherein phenyl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of chloro and carboxy.

Embodiments of the present invention include those compounds wherein atleast one R³ substituent is phenyl.

Embodiments of the present invention include those compounds wherein R³is a substituent selected from the group consisting of methyl and phenyloptionally substituted with one to two substituents independentlyselected from the group consisting of chloro and carboxy.

Embodiments of the present invention include those compounds wherein R⁴is C₆₋₁₀aryl optionally substituted with one to three R⁴¹ substituentsindependently selected from the group consisting of (C₁₋₃)alkyl,(C₁₋₆)alkoxy, phenyl(C₁₋₆)alkoxy; hydroxy; halogen; formylamino;aminocarbonyl; C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl;heterocyclylcarbonyl wherein heterocyclyl is a 5-7 memberednitrogen-containing ring and said heterocyclyl is attached to thecarbonyl carbon via a nitrogen atom; carboxy; and cyano; provided thatno more than one R⁴¹ substituent is formylamino, aminocarbonyl,C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl, heterocyclylcarbonyl,hydroxy, carboxy, or a phenyl-containing substituent.

Embodiments of the present invention include those compounds wherein R⁴is phenyl substituted with one to three R⁴¹ substituents independentlyselected from the group consisting of (C₁₋₃)alkyl, (C₁₋₃)alkoxy,phenyl(C₁₋₃)alkoxy, hydroxy, C₁₋₆alkylaminocarbonyl, and aminocarbonyl;provided that no more than one R⁴¹ substitutent is aminocarbonyl,C₁₋₆alkylaminocarbonyl, hydroxy, or a phenyl-containing substituent.

Embodiments of the present invention include those compounds wherein R⁴is phenyl substituted at the 4-position with hydroxy,C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and optionally substitutedwith one to two substituents independently selected from the groupconsisting of methyl, methoxy, and benzyloxy.

Embodiments of the present invention include those compounds wherein R⁴is phenyl substituted at the 4-position with hydroxy,C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and optionally substitutedwith one to two methyl substituents.

Embodiments of the present invention include those compounds wherein R⁴is phenyl substituted at the 4-position with hydroxy,C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and substituted at the 2- and6-positions with methyl substituents.

Embodiments of the present invention include those compounds wherein R⁵is hydrogen or methyl.

Embodiments of the present invention include those compounds wherein R⁵is hydrogen.

Embodiments of the present invention include those compounds wherein R⁶is hydrogen or methyl.

Embodiments of the present invention include those compounds wherein R⁶is hydrogen.

Embodiments of the present invention include those compounds wherein R⁷is hydrogen or methyl.

Embodiments of the present invention include those compounds wherein R⁷is hydrogen.

Embodiments of the present invention include those compounds whereinR^(a) and R^(b) are independently selected from the group consisting ofhydrogen and C₁₋₃alkyl; or, when R^(a) and R^(b) are each other thanhydrogen or C1-6 alkoxycarbonyl, R^(a) and R^(b) are optionally takentogether with the nitrogen atom to which they are both attached to forma five to seven membered monocyclic ring.

Embodiments of the present invention include those compounds whereinR^(a) and R^(b) are independently hydrogen or methyl.

Embodiments of the present invention include those compounds whereinR^(a) and R^(b) are each hydrogen.

Embodiments of the present invention include those compounds wherein Lis O.

Embodiments of the present invention include those compounds that arepresent in their RR, SS, RS, or SR configuration.

Embodiments of the present invention include those compounds that arepresent in their S,S configuration.

An aspect of the present invention includes compounds of Formula (Ia):

wherein:R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl(C₁₋₄)alkyl, and heteroaryl(C₁₋₄)alkyl;

-   wherein the aryl and heteroaryl portion of aryl(C₁₋₄)alkyl and    heteroaryl(C₁₋₄)alkyl are optionally substituted with one to three    R¹¹ substituents independently selected from the group consisting of    C₁₋₆alkoxy; heteroaryl optionally substituted with one to two    substituents independently selected from the group consisting of    C₁₋₄alkyl, C₁₋₄alkoxy, and carboxy; carboxy; C₁₋₄alkoxycarbonyloxy;    C₁₋₄alkoxycarbonyl; aminocarbonyl; C₁₋₄alkylaminocarbonyl;    C₃₋₆cycloalkylaminocarbonyl; hydroxy(C₁₋₆)alkylaminocarbonyl;    C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is optionally substituted    with carboxy or C₁₋₄alkoxycarbonyl; heterocyclylcarbonyl; cyano;    halogen; trifluoromethoxy; and hydroxy; provided that no more than    one R¹¹ is heteroaryl (optionally substituted with one to two    C₁₋₄alkyl substituents); C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is    optionally substituted with carboxy or C₁₋₄alkoxycarbonyl; or    heterocyclylcarbonyl;-   R² is selected from the group consisting of hydrogen, C₁₋₄alkyl,    hydroxy(C₁₋4)alkyl, and phenyl(C₁₋₆)alkoxy(C₁₋₄)alkyl;-   wherein said phenyl is optionally substituted with one to two    substituents independently selected from the group consisting of    C₁₋₃alkyl, C₁₋₃alkoxy, hydroxy, cyano, fluorine, chlorine, bromine,    trifluoromethyl, and trifluoromethoxy;-   R³ is one to two substituents independently selected from the group    consisting of C₁₋₆alkyl, halogen, and aryl; wherein aryl is    optionally substituted with one to three substituents independently    selected from the group consisting of halogen, carboxy,    aminocarbonyl, C₁₋₃alkylsulfonylamino, cyano, hydroxy, amino,    C₁₋₃alkylamino, and (C₁₋₃alkyl)₂amino;-   R⁴ is C₆₋₁₀aryl optionally substituted with one to three R⁴¹    substituents independently selected from the group consisting of    (C₁₋₃)alkyl, (C₁₋₆)alkoxy, phenyl(C₁₋₆)alkoxy; hydroxy; halogen;    formylamino; aminocarbonyl; C₁₋₆alkylaminocarbonyl;    (C₁₋₆alkyl)₂aminocarbonyl; heterocyclylcarbonyl wherein heterocyclyl    is a 5-7 membered nitrogen-containing ring and said heterocyclyl is    attached to the carbonyl carbon via a nitrogen atom; carboxy; and    cyano;    provided that no more than one R⁴¹ substituent is formylamino,    aminocarbonyl, C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl,    heterocyclylcarbonyl, hydroxy, carboxy, or a phenyl-containing    substituent.-   R⁵ is hydrogen or methyl;-   R^(a) and R^(b) are independently hydrogen or C₁₋₃alkyl; or, when    R^(a) and R^(b) are each other than hydrogen, R^(a) and R^(b) are    optionally taken together with the nitrogen atom to which they are    both attached to form a five to seven membered monocyclic ring;    and pharmaceutically acceptable enantiomers, diastereomers,    racemates, and salts thereof.

Another aspect of the present invention is directed to a compound ofFormula (Ia) wherein:

-   R¹ is selected from the group consisting of C₆₋₁₀aryl(C₁₋₄)alkyl,    pyridinyl(C₁₋₄)alkyl, and furanyl(C₁₋₄)alkyl; wherein C₆₋₁₀aryl,    pyridinyl, and furanyl are optionally substituted with one to three    R¹¹ substituents independently selected from the group consisting of    C₁₋₃alkoxy; tetrazolyl; carboxy; C₁₋₃alkoxycarbonyl; aminocarbonyl;    C₁₋₄alkylaminocarbonyl; C₁₋₃alkylaminocarbonyl;    C₃₋₆cycloalkylaminocarbonyl; hydroxy(C₁₋₄)alkylaminocarbonyl;    C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is optionally substituted    with carboxy or C₁₋₄alkoxycarbonyl; morpholin-4-ylcarbonyl; cyano;    halogen; and trifluoromethoxy; provided that no more than one R¹¹ is    C₆₋₁₀arylaminocarbonyl;-   R² is hydrogen or C₁₋₄alkyl;-   R³ is one to two substituents independently selected from the group    consisting of C₁₋₃alkyl, bromo, and phenyl; wherein phenyl is    optionally substituted with one to three substituents independently    selected from the group consisting of chloro, fluoro, carboxy,    aminocarbonyl, and cyano;-   R⁴ is phenyl substituted with one to three R⁴¹ substituents    independently selected from the group consisting of (C₁₋₃)alkyl,    (C₁₋₃)alkoxy, phenyl(C₁₋₃)alkoxy, hydroxy, C₁₋₆alkylaminocarbonyl,    and aminocarbonyl; provided that no more than one R⁴¹ is    aminocarbonyl, C₁₋₆alkylaminocarbonyl, hydroxy, or a    phenyl-containing substituent;-   R⁵ is hydrogen;-   R^(a) and R^(b) are independently hydrogen or methyl;-   and pharmaceutically acceptable enantiomers, diastereomers,    racemates, and salts thereof.

Another aspect of the present invention is directed to a compound ofFormula (Ia) wherein:

-   R¹ is selected from the group consisting of phenyl(C₁₋₃)alkyl,    pyridinyl(C₁₋₃)alkyl, and furanyl(C₁₋₃)alkyl; wherein phenyl,    pyridinyl, and furanyl are optionally substituted with one to three    R¹¹ substituents independently selected from the group consisting of    C₁₋₃alkoxy; tetrazolyl, C₃₋₆cycloalkylaminocarbonyl;    hydroxy(C₁₋₄)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl wherein    C₆₋₁₀aryl is optionally substituted with carboxy or    C₁₋₄alkoxycarbonyl; morpholin-4-ylcarbonyl; chloro; fluoro;    trifluoromethoxy; and carboxy;-   R² is hydrogen or methyl;-   R³ is one to two substituents independently selected from the group    consisting of methyl and phenyl; wherein phenyl is optionally    substituted with one to three substituents independently selected    from the group consisting of chloro and carboxy;-   R⁴ is phenyl substituted at the 4-position with hydroxy,    C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and optionally substituted    with one to two substituents independently selected from the group    consisting of methyl, methoxy, and benzyloxy;-   R⁵ is hydrogen;-   R^(a) and R^(b) are each hydrogen;-   and pharmaceutically acceptable enantiomers, diastereomers,    racemates, and salts thereof.

Another embodiment is directed to compounds of Formula (Ib):

wherein in one embodiment of this invention the variables are aspreviously defined. In another embodiment of the present invention L isoxygen and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependentlyselected from the group consisting of:

TABLE I Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b) 1 2-Aminocarbonyl- methylphenyl H H 2,6-dimethyl-4- H phenylmethyl aminocarbonyl 2 2-Cyano-phenylmethyl phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 32-Bromo-phenyl methyl phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl4 3-Carboxy-4- methyl phenyl H H 4-amino- H methoxy-phenyl carbonylmethyl 5 3-Carboxy-4- H phenyl H H 4-amino- H methoxy-phenyl carbonylmethyl 6 3-Carboxy-4- H phenyl H H 2,6-dimethyl-4- H methoxy-phenylaminocarbonyl methyl 7 3-Methoxy- H phenyl H H 2,6-dimethyl-4- Hcarbonyl- aminocarbonyl 4-methoxy- phenylmethyl 8 3-(1H-tetrazol-5-methyl phenyl H H 2,6-dimethyl-4- H yl)-4-methoxy- aminocarbonylphenylmethyl 9 3-Methoxy- methyl phenyl H H 2,6-dimethyl-4- H carbonyl-aminocarbonyl phenylmethyl 10 3-Methoxy methyl naphthalen-1-yl H H2,6-dimethyl-4- H carbonyl- aminocarbonyl phenylmethyl 11 3-Carboxy-methyl naphthalen-1-yl H H 2,6-dimethyl-4- H phenylmethyl aminocarbonyl12 3-Carboxy- methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H phenylmethylaminocarbonyl 13 4-Carboxy- methyl naphthalen-1-yl H H 2,6-dimethyl-4- Hphenylmethyl aminocarbonyl 14 3-Methoxy-4- methyl phenyl H H2,6-dimethyl-4- H carboxy- aminocarbonyl phenylmethyl 15 3,4-Dihydroxy-methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl hydroxy 16Piperidin-4-yl methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy 173-Methoxy methyl phenyl H H 2,6-dimethyl-4- H carbonyl-4- aminocarbonylmethoxy- phenylmethyl 18 3-Carboxy-4- methyl phenyl H H 2,6-dimethyl-4-H methoxy- aminocarbonyl phenylmethyl 19 3,4-Dimethoxy- methyl3-bromophenyl H H 2,6-dimethyl-4- H phenylmethyl aminocarbonyl 203,4-Dimethoxy- methyl 3-carboxyphenyl H H 2,6-dimethyl-4- H phenylmethylaminocarbonyl 21 3,4-Dimethoxy- benzyloxy- phenyl H H 2,6-dimethyl-4- Hphenylmethyl methyl hydroxy 23 3,4-Dimethoxy- methyl 3-aminocarbonyl H H2,6-dimethyl-4- H phenylmethyl phenyl aminocarbonyl 24 3,4-Dimethoxy-methyl 3-cyanophenyl H H 2,6-dimethyl-4- H phenylmethyl aminocarbonyl 25Isopropyl H quinoxalin-8-yl Me H 2,6-dimethyl-4- H hydroxy 263,4-Dimethoxy- methyl 2-bromophenyl H H 2,6-dimethyl-4- H phenylmethylaminocarbonyl 27 3,4-Dimethoxy- methyl 2-cyanophenyl H H 2,6-dimethyl-4-H phenylmethyl aminocarbonyl 28 3,4-Dimethoxy- methyl 2-aminocarbonyl HH 2,6-dimethyl-4- H phenylmethyl phenyl aminocarbonyl 29 3,4-Dimethoxy-methyl 2-carboxyphenyl H H 2,6-dimethyl-4- H phenylmethyl aminocarbonyl30 3,4-Dibenzyloxy- methyl phenyl H H 2,6-dimethyl-4- H phenylmethylhydroxy 31 [1,3]benzo methyl phenyl H H 2,6-dimethyl, 4- H dioxal-5-ylhydroxy 32 4-Methoxy- methyl phenyl H H 2,6-dimethyl-4- H phenylmethylhydroxy 33 3-Methoxy- methyl phenyl H H 2,6-dimethyl-4- H phenylmethylhydroxy 34 2,4-Dimethoxy- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl hydroxy 35 3,4-Dimethoxy- H phenyl H H 2,6-dimethyl-4- Hphenylmethyl hydroxy 36 Isopropyl H 4-methylcarbonyl H H 2,6-dimethyl-4-H phenyl hydroxy 37 Isopropyl H 3-fluoro, 4- Me H 2,6-dimethyl-4- Hcarboxy-phenyl hydroxy 38 Isopropyl H 2-phenyl- Me H 2,6-dimethyl-4- Hethylen-1-yl hydroxy 39 Isopropyl H 4-hydroxymethyl Me H 2,6-dimethyl-4-H phenyl hydroxy 40 Benzhydryl H phenyl H H 2,6-dimethyl-4- H hydroxy 41Isopropyl H 4-cyanophenyl Me H 2,6-dimethyl-4- H hydroxy 42 Benzylmethyl 4-trifluoromethyl H H 2,6-dimethyl-4- H phenyl aminocarbonyl 43Isopropyl H 3- Me H 2,6-dimethyl-4- H trifluoromethoxy hydroxy phenyl 44Isopropyl H 4- Me H 2,6-dimethyl-4- H trifluoromethoxy hydroxy phenyl 45Isopropyl H 3- Me H 2,6-dimethyl-4- H methanesulfonyl hydroxyaminophenyl 46 Isopropyl H 4-(2- Me H 2,6-dimethyl-4- H carboxyethyl)hydroxy phenyl 47 Isopropyl H 3-amino-5- Me H 2,6-dimethyl-4- Hcarboxyphenyl hydroxy 48 3-Carboxy- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl hydroxy 49 4-Carboxy- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl carboxy 50 4-Carboxy- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl aminocarbonyl 51 4-Methoxy methyl phenyl H H2,6-dimethyl-4- H carbonyl- aminocarbonyl phenylmethyl 52 3-Methoxymethyl phenyl H H 2,6-dimethyl-4- H carbonyl- hydroxy phenylmethyl 531-Benzyloxy methyl phenyl H H 2,6-dimethyl-4- H carbonyl- hydroxypiperadin-4- ylmethyl 54 Furan-2-yl methyl phenyl H H 2,6-dimethyl-4- Hmethyl hydroxy 55 Furan-3-yl methyl phenyl H H 2,6-dimethyl-4- H methylhydroxy 56 Cyclohexyl methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy57 Pyridin-4-yl methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy 58Benzyl methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H aminocarbonyl 59Benzyl methyl 3-fluorophenyl H H 2,6-dimethyl-4- H aminocarbonyl 60Isopropyl H 3-cyanophenyl Me H 2,6-dimethyl-4- H hydroxy 61 Isopropyl H2,5-difluorophenyl Me H 2,6-dimethyl-4- H hydroxy 62 Isopropyl H 4- Me H2,6-dimethyl-4- H methanesulfonyl hydroxy phenyl 64 Benzyl benzyloxyphenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 65 Isopropyl H Br Me H2,6-dimethyl-4- H hydroxy 66 Isopropyl H 4-dimethylamino Me H2,6-dimethyl-4- H phenyl hydroxy 67 Isopropyl H 3-dimethylamino Me H2,6-dimethyl-4- H carbonylphenyl hydroxy 68 Isopropyl H 3-hydroxyphenylMe H 2,6-dimethyl-4- H hydroxy 69 Isopropyl H 4-aminocarbonyl Me H2,6-dimethyl-4- H phenyl hydroxy 70 Isopropyl H 3-chlorophenyl Me H2,6-dimethyl-4- H hydroxy 71 Isopropyl H 2,4-difluorophenyl Me H2,6-dimethyl-4- H hydroxy 72 Isopropyl H 3-methanesulfonyl Me H2,6-dimethyl-4- H phenyl hydroxy 73 Isopropyl H 3-aminocarbonyl Me H2,6-dimethyl-4- H phenyl hydroxy 74 Benzyl methyl 4-trifluoromethyl Me H2,6-dimethyl-4- H phenyl aminocarbonyl 75 3,4-Dimethoxy- methyl phenyl HH 2,6-dimethyl-4- H phenylmethyl aminocarbonyl 76 Benzyl methyl4-fluorophenyl H H 2,6-dimethyl-4- H aminocarbonyl 77 4-Dimethylamino-methyl phenyl H Me 2,6-dimethyl-4- H phenylmethyl hydroxy 784-Methylamino- methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl hydroxy79 4-Methylcarbonyl methyl phenyl H H 2,6-dimethyl-4- H amino-phenylhydroxy methyl 80 4-Carboxy- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl hydroxy 81 4-Hydroxy- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl hydroxy 83 Benzyl methyl 4-fluorophenyl H H 2,6-dimethyl-4-H hydroxy 84 Isopropyl methyl 4-fluorophenyl H H 2,6-dimethyl-4- Hhydroxy 85 Isopropyl hydroxy phenyl H H 2,6-dimethyl-4- H methylaminocarbonyl 86 Isopropyl H phenyl H H 2,6-dimethyl, 4- H aminocarbonyl87 3,4-Dichloro- H phenyl H H 2,6-dimethyl-4- H phenylmethyl hydroxy 884-Methylcarbonyl methyl phenyl H H 2,6-dimethyl-4- H oxy-phenyl hydroxymethyl 89 4-Methoxycarbonyl- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl hydroxy 90 3-Aminocarbonyl- methyl phenyl H H2,6-dimethyl-4- H phenylmethyl hydroxy 91 3-Cyano-phenyl methyl phenyl HH 2,6-dimethyl-4- H methyl hydroxy 92 Pyridin-3-yl methyl phenyl H H2,6-dimethyl-4- H methyl hydroxy 93 Pyridin-2-yl methyl phenyl H H2,6-dimethyl-4- H methyl hydroxy 94 1-(R)-Phenylethyl H phenyl H H2,6-dimethyl-4- H aminocarbonyl 95 1-(S)-Phenylethyl H phenyl H H2,6-dimethyl-4- H aminocarbonyl 96 2-Methoxy- methyl phenyl H H2,6-dimethyl-4- H phenylmethyl hydroxy 97 2,6-Dichloro- methyl phenyl HH 2,6-dimethyl-4- H phenylmethyl hydroxy 98 3-Phenoxy- methyl phenyl H H2,6-dimethyl-4- H phenylmethyl hydroxy 99 Naphthalen-1-yl- methyl phenylH H 2,6-dimethyl-4- H methyl hydroxy 100 Naphthalen-2-yl- methyl phenylH H 2,6-dimethyl-4- H methyl hydroxy 101 3-Bromo-phenyl methyl phenyl HH 2,6-dimethyl-4- H methyl hydroxy 102 3,4-Dimethoxy- methyl phenyl H H2,6-dimethyl-4- H phenylmethyl hydroxy 103 2,4-Dichloro- methyl phenyl HH 2,6-dimethyl-4- H phenylmethyl hydroxy 104 Benzyl isobutyl phenyl H H2,6-dimethyl-4- H hydroxy 105 Benzyl benzyl phenyl H H 2,6-dimethyl-4- Hhydroxy 106 Benzyl isopropyl phenyl H H 2,6-dimethyl-4- H hydroxy 107Benzyl H phenyl H H 2,6-dimethyl-4- H aminocarbonyl 108 3-Phenyl methylphenyl H H 2,6-dimethyl-4- H prop-1-yl aminocarbonyl 109 2-Phenylethylmethyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 111 1-Phenylethylmethyl phenyl H H 2,6-dimethyl-4- H diastereomer A aminocarbonyl 1121-Phenylethyl methyl phenyl H H 2,6-dimethyl-4- H diasteromer Baminocarbonyl 114 Benzyl methyl phenyl H H 2,6-dimethyl-4- Haminocarbonyl 115 Isopropyl H 4-biphenyl Me H 2,6-dimethyl-4- H hydroxy116 Isopropyl H 3-fluorophenyl Me H 2,6-dimethyl-4- H hydroxy 117Isopropyl H 2-fluorophenyl Me H 2,6-dimethyl-4- H hydroxy 118 Isopropylhydroxy phenyl H H 2,6-dimethyl-4- H methyl hydroxy 119 H hydroxy phenylH H 2,6-dimethyl-4- H methyl hydroxy 120 Isopropyl 3-(amino phenyl H H2,6-dimethyl-4- H methyl) hydroxy phenyl methyl 121 Isopropyl 3-aminophenyl H H 2,6-dimethyl-4- H carbonyl hydroxy phenyl methyl 122Isopropyl 3-cyano phenyl H H 2,6-dimethyl-4- H phenyl hydroxy methyl 123Isopropyl H 4-carboxyphenyl Me H 2,6-dimethyl-4- H hydroxy 124 IsopropylH pyridin-3-yl Me H 2,6-dimethyl-4- H hydroxy 125 Isopropyl H4-methoxyphenyl Me H 2,6-dimethyl-4- H hydroxy 126 Isopropyl H3,5-difluorophenyl Me H 2,6-dimethyl-4- H hydroxy 127 Cyclohexyl methylphenyl H H 2,6-dimethyl-4- H aminocarbonyl 129 Carboxymethyl H phenyl HH 2,6-dimethyl-4- H hydroxy 130 Isopropyl H 3-hydroxymethyl Me H2,6-dimethyl-4- H phenyl hydroxy 131 Isopropyl H pyrimidin-5-yl Me H2,6-dimethyl-4- H hydroxy 132 Isopropyl H pyrimidin-5-yl Me H 4-hydroxyH 133 Isopropyl H 3-carboxyphenyl Me H 2,6-dimethyl-4- H hydroxy 134Isopropyl H 3-biphenyl Me H 2,6-dimethyl-4- H hydroxy 135 Isopropyl H2-methoxyphenyl Me H 2,6-dimethyl-4- H hydroxy 136 Isopropyl benzylphenyl H H 3-aminocarbonyl H 137 Isopropyl isopropyl phenyl H H3-aminocarbonyl H 138 Isopropyl benzyloxy phenyl H H 2,6-dimethyl-4- Hmethyl hydroxy 139 Isopropyl isobutyl phenyl H H 2,6-dimethyl-4-[2- H(2,6-dimethyl-4- hydroxyphenyl)-1- amino- ethylcarbonxyloxy] phenyl 140Isopropyl isobutyl phenyl H H 2,6-dimethyl-4- H hydroxy 141 Isopropyl H3,5- Me H 2,6-dimethyl-4- H dichlorophenyl hydroxy 142 Isopropyl H3-methoxyphenyl Me H 2,6-dimethyl-4- H hydroxy 143 Isopropyl methylphenyl H H 2,6-dimethyl-4- H aminocarbonyl 145 Isopropyl H 2-biphenyl MeH 2,6-dimethyl-4- H hydroxy 146 Isopropyl H thiophen-3-yl Me H2,6-dimethyl-4- H hydroxy 147 Isopropyl H 4-chlorophenyl Me H2,6-dimethyl-4- H hydroxy 148 Isopropyl H 3-methylcarbonyl Me H2,6-dimethyl-4- H aminophenyl hydroxy 149 Isopropyl H 4-trifluoromethylMe H 2,6-dimethyl-4- H phenyl hydroxy 150 Isopropyl H naphthalen-2-yl MeH 2,6-dimethyl-4- H hydroxy 151 Isopropyl H 2-trifluoromethyl Me H2,6-dimethyl-4- H phenyl hydroxy 152 Isopropyl H thiophen-3-yl Me H4-hydroxy H 153 Isopropyl H pyridin-3-yl Me H 4-hydroxy H 154 IsopropylH phenyl Me H 4-hydroxy H 155 Isopropyl H 2-chlorophenyl Me H2,6-dimethyl-4- H hydroxy 156 Isopropyl H naphthalen-1-yl Me H2,6-dimethyl-4- H hydroxy 157 Isopropyl benzyl phenyl H H 3-cyano H 158Isopropyl benzyl phenyl H H 4-hydroxy H 159 Isopropyl benzyl phenyl H H2,6-dimethyl-4- H hydroxy 160 Isopropyl isopropyl phenyl H H 3-cyano H161 Isopropyl isopropyl phenyl H H 4-hydroxy H 162 Isopropyl isopropylphenyl H H 2,6-dimethyl-4- H hydroxy 163 Isopropyl H 4-fluorophenyl Me H2,6-dimethyl-4- H hydroxy 164 Isopropyl H 3,5-bis- Me H 2,6-dimethyl-4-H trifluoromethyl hydroxy phenyl 165 Isopropyl H 2-methylphenyl Me H2,6-dimethyl-4- H hydroxy 166 Isopropyl H phenyl Me H 2,6-dimethyl-4- Hhydroxy 167 2-Dimethylamino- H phenyl H H 2,6-dimethyl-4- H1-methyl-eth-1-yl hydroxy 168 Methyl isobutyl phenyl H H 3-aminocarbonylH 169 Methyl isobutyl phenyl H H 3-cyano H 170 Ethyl isopropyl phenyl HH 2,6-dimethyl-4- H hydroxy 171 Methyl isopropyl phenyl H H 4-hydroxy H172 H 3-amino phenyl H H 2,6-dimethyl-4- H carbonyl hydroxy phenylmethyl 173 H 3-cyano phenyl H H 2,6-dimethyl-4- H phenyl hydroxy methyl174 Methyl isobutyl phenyl H H 2,6-dimethyl-4- H hydroxy 175 H benzyloxyphenyl H H 2,6-dimethyl-4- H methyl hydroxy 176 H isobutyl phenyl H H2,6-dimethyl-4- H hydroxy 177 H benzyl phenyl H H 2,6-dimethyl-4- Hhydroxy 178 Isopropyl H phenyl H H 2,6-dimethyl-4- H aminocarbonyl 179Methyl methyl phenyl H H 2,6-dimethyl-4- H morpholin-1- ylcarbonyl 181Methyl methyl phenyl H H 2,6-dimethyl-4- H ethyl aminocarbonyl 183Methyl methyl phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 185 Hisopropyl phenyl H H 3-aminocarbonyl H 186 H isopropyl phenyl H H3-cyano H 187 H isopropyl phenyl H H 2,6-dimethyl-4- H hydroxy 188 Hisopropyl phenyl H H 4-hydroxy H 189 Methyl methyl phenyl H H4-aminosulfonyl H 190 Cyclohexyl H phenyl H H 2,6-dimethyl-4- H hydroxy191 Cyclohexyl H phenyl H H 4-hydroxy H 192 Cyclopropyl H phenyl H H2,6-dimethyl-4- H methyl hydroxy 193 Cyclopropyl H phenyl H H 4-hydroxyH methyl 194 Isopropyl H phenyl H H 2,6-dimethyl-4- H hydroxy 195Isopropyl H phenyl H H 4-hydroxy H 196 Methyl methyl phenyl H H2,6-dimethyl-4- H aminocarbonyl 197 Ethyl methyl phenyl H H2,6-dimethyl-4- H aminocarbonyl 198 Methyl H phenyl H H 4-hydroxy H 199Methyl H phenyl H H 2,6-dimethyl-4- H hydroxy 202 Methyl methyl phenyl HH 4-aminocarbonyl H 204 Methyl methyl benzyl H H 4-hydroxy H 205 Methylmethyl benzyl H H 2,6-dimethyl-4- H hydroxy 207 Methyl methyl phenyl H H2,6-dimethyl-4- H hydroxy 209 H methyl phenyl H H 2,6-dimethyl-4- Hhydroxy 211 Methyl methyl phenyl H H 4-hydroxy H 213 H methyl phenyl H H4-hydroxy H 215 Ethyl methyl phenyl H H 4-hydroxy H 216 Ethyl methylphenyl H H 2,6-dimethyl-4- H hydroxy 218 Benzyl methyl phenyl H H2,6-dimethyl-4- H hydroxy 219 Benzyl methyl phenyl H H 4-hydroxy H 224Isopropyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 225 Isopropylmethyl phenyl H H 4-hydroxy H 226 2-Carboxy-phenyl methyl phenyl H H2,6-dimethyl-4- H methyl aminocarbonyl 227 3-Carboxy-phenyl methylphenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 229 2-Bromo-4,5-methyl phenyl H H 2,6-dimethyl-4- H dimethoxy- aminocarbonylphenylmethyl 230 2-Carboxy-4,5- methyl phenyl H H 2,6-dimethyl-4- Hdimethoxy- aminocarbonyl phenylmethyl 231 3-Carboxy-4- methyl phenyl H HH H methoxy-phenyl methyl 232 3-Carboxy-4- methyl phenyl H H2,6-dimethyl H methoxy-phenyl methyl 233 3-Methoxy- methyl phenyl H H2,6-dimethyl H carbonyl- 4-methoxy- phenylmethyl 234 3,4-Dimethoxy-methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl imidazol-2-yl 2363,4-Dimethoxy- methyl phenyl H H 2,6-dimethyl H phenylmethyl 2373-Carboxy-4- methyl 4-chlorophenyl H H 2,6-dimethyl-4- H methoxy-phenylaminocarbonyl methyl 238 3-Carboxy, 4- methyl 4-fluorophenyl H H2,6-dimethyl-4- H methoxy-phenyl aminocarbonyl methyl 239 3-Carboxy-4-methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H methoxy-phenylaminocarbonyl methyl 240 4-Carboxy-phenyl methyl 4-chlorophenyl Me H2,6-dimethyl-4- H methyl aminocarbonyl 241 3-Carboxy-4- methyl4-chlorophenyl Cl H 2,6-dimethyl-4- H methoxy-phenyl aminocarbonylmethyl 242 3-(1H-tetrazol-5- methyl phenyl H H 2,6-dimethyl-4- Hyl)-phenylmethyl aminocarbonyl 243 3-Carboxy-4- methyl phenyl H H2,6-dimethyl-4- H trifluoromethoxy- aminocarbonyl phenylmethyl 244Bis-3,4- methyl phenyl H H 2,6-dimethyl-4- H trifluoromethoxy-aminocarbonyl phenylmethyl 245 3-Carboxy-phenyl methyl phenyl H H2,6-dimethyl-4- H methyl aminocarbonyl 246 Quinolin-4-yl methyl phenyl HH 2,6-dimethyl-4- H methyl hydroxy 247 4-Methoxy methyl phenyl H H2,6-dimethyl-4- H naphthalen-1- hydroxy ylmethyl 248 4- methyl phenyl HH 2,6-dimethyl-4- H Trifluoromethoxy- hydroxy phenylmethyl 2494-Trifluoromethyl- methyl phenyl H H 2,6-dimethyl-4- H phenylmethylhydroxy 250 4-Isopropyloxy- methyl phenyl H H 2,6-dimethyl-4- Hphenylmethyl hydroxy 251 3-Ethoxyphenyl- methyl phenyl H H2,6-dimethyl-4- H methyl hydroxy 252 5- methyl phenyl H H2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-2-ylmethyl 2535-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H pyridin-2-ylmethylaminocarbonyl 254 6-Carboxy- methyl phenyl H H 2,6-dimethyl-4- Hpyridin-3-ylmethyl aminocarbonyl 255 6- methyl phenyl H H2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-3-ylmethyl 2565-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H furan-2-ylmethylaminocarbonyl 257 5- methyl phenyl H H 2,6-dimethyl-4- HMethoxycarbonyl- aminocarbonyl furan-2-ylmethyl 258 3,4-Dimethoxy-hydroxy phenyl H H 2,6-dimethyl-4- H phenylmethyl methyl aminocarbonyl259 Benzyl hydroxy phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 2603-Carboxy-4- methyl phenyl H H 2,6-dimethyl-4- H methoxy-phenyl hydroxymethyl 261 3-Carboxy-4- methyl phenyl H H 4-hydroxy H methoxy-phenylmethyl 262 3-Carboxy-4- methyl phenyl H H 4-hydroxy H/Me methoxy-phenylmethyl 263 3-Carboxy-4- H phenyl H H 4-hydroxy H methoxy-phenyl methyl264 3-Carboxy-4- H phenyl H H 4-hydroxy H/Me methoxy-phenyl methyl 2653-Carboxy-4- H phenyl H H 2,6-dimethyl-4- H methoxy-phenyl hydroxymethyl 266 3-Methoxy- methyl phenyl H H H H carbonyl- 4-methoxy-phenylmethyl 267 3-(1H-tetrazol-5- methyl phenyl H H 4-amino- Hyl)-phenylmethyl carbonyl 268 3-Methoxy- methyl phenyl H H2,6-dimethyl-4- H carbonyl- hydroxy 4-methoxy- phenylmethyl 2693-Methoxy- methyl phenyl H H 4-amino- H carbonyl carbonyl 270 3-Carboxymethyl phenyl H H 4-aminocarbonyl H 271 3-Methoxy- H phenyl H H2,6-dimethyl-4- H carbonyl aminocarbonyl 272 3-Carboxy H phenyl H H2,6-dimethyl-4- H aminocarbonyl 274 3-Carboxy-4- methyl phenyl H H4-benzyloxy H/Me methoxy- phenylmethyl 275 3-Carboxy-4- methyl phenyl HH 4-amino- H methoxy- carbonyl phenylmethyl 277 3-Carboxy-phenyl methyl4-chlorophenyl Me H 4-amino- H carbonyl 279 3-Methoxy- methyl phenyl H H4-hydroxy H carbonyl- 4-methoxy- phenylmethyl 286 5- methyl phenyl H H2,6-dimethyl-4- H Methoxycarbonyl- hydroxy furan-2-ylmethyl 2875-Carboxy-furan- methyl phenyl H H 2,6-dimethyl-4- H 2-yl methyl hydroxy288 3-Carboxy-4- methyl 3-bromophenyl H H 2,6-dimethyl-4- H methoxy-aminocarbonyl phenylmethyl 289 3-Carboxy-4- methyl 4-iodophenyl H H2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 290 3-Carboxy-4-methyl 2-bromophenyl H H 2,6-dimethyl-4- H methoxy- aminocarbonylphenylmethyl 291 3-Carboxy-4- methyl 4-bromophenyl H H 2,6-dimethyl-4- Hmethoxy- aminocarbonyl phenylmethyl 292 3-Carboxy-4- methyl phenyl H H2,6-dimethyl H methoxy- phenylmethyl 293 3-Carboxy-4- methyl4-chlorophenyl methyl H 4-hydroxy H methoxy- phenylmethyl 2953-Aminocarbonyl- methyl phenyl H H 2,6-dimethyl-4- H 4-methoxyaminocarbonyl phenylmethyl 296 3-(Morpholin-4- methyl phenyl H H2,6-dimethyl-4- H ylcarbonyl)-4- aminocarbonyl methoxy phenylmethyl 297-3-Aminocarbonyl- methyl phenyl H H 4-hydroxy H 4-methoxy- phenylmethyl298 3-(Morpholin-4- methyl phenyl H H 4-hydroxy H ylcarbonyl)-4-methoxy- phenylmethyl 299 3-(2-Hydroxy methyl phenyl H H 2,6-dimethyl-4-H eth-1-yl- aminocarbonyl aminocarbonyl)-4- methoxy phenylmethyl 3003-(Cyclopropyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl)-4-aminocarbonyl methoxy- phenylmethyl 301 3-(Phenylamino methyl phenyl H H2,6-dimethyl-4- H carbonyl )-4- aminocarbonyl methoxy- phenylmethyl 3035- methyl phenyl H H 4-amino- H Methoxycarbonyl- carbonylfuran-2-ylmethyl 304 5-Carboxy-furan- methyl phenyl H H 4-amino- H 2-ylmethyl carbonyl 305 3-(Phenylamino methyl phenyl H H 2,6-dimethyl-4- Hcarbonyl )-4- hydroxy methoxy- phenylmethyl 306 3-(3- methyl phenyl H H2,6-dimethyl-4- H carboxyphenyl hydroxy aminocarbonyl)-4- methoxy-phenylmethyl 307 3-(1H-Tetrazol-5- methyl phenyl H H 2,6-dimethyl-4- Hyl)-4-methoxy- hydroxy phenylmethyl 308 3-(4- methyl phenyl H H2,6-dimethyl-4- H Carboxyphenyl hydroxy aminocarbonyl)-4- methoxy-phenylmethyl 309 3-(2-t-Butyl- methyl phenyl H H 2,6-dimethyl-4- Htetrazol-5-yl)-4- aminocarbonyl methoxy- phenylmethyl 310 3-Methoxy-methyl phenyl H H 2,6-dimethyl-4- Methoxy carbonyl- aminocarbonylcarbonyl 4-methoxy- phenylmethyl 311 2-Methoxycarbonyl- methyl phenyl HH 2,6-dimethyl-4- H pyridin-4-ylmethyl aminocarbonyl 312 4- methylphenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonylpyridin-2-ylmethyl 313 6- methyl phenyl H H 2,6-dimethyl-4- HMethoxycarbonyl- aminocarbonyl pyridin-2-ylmethyl 315 3-Methoxy- methylphenyl H H 2,6-dimethyl-4- Methoxy carbonyl- aminocarbonyl carbonyl4-methoxy- phenylmethyl 316 2-Carboxy-pyridin- methyl phenyl H H2,6-dimethyl-4- H 4-ylmethyl aminocarbonyl 317 6-Carboxy-pyridin- methylphenyl H H 2,6-dimethyl-4- H 2-ylmethyl aminocarbonyl

Exemplified compounds of the present invention include compounds ofFormula (Ic):

wherein in one embodiment of this invention the variables are aspreviously defined. In another embodiment of the present invention L isO and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependentlyselected from the group consisting of:

TABLE II Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b) 22 3,4-Dimethoxy-benzyloxy phenyl H H 2,6-dimethyl-4- H phenylmethyl methyl hydroxy 63Isopropyl hydroxy phenyl H H 2,6-dimethyl-4- H methyl hydroxy 82Isopropyl methyl 4-fluorophenyl H H 2,6-dimethyl-4- H hydroxy 1102-Phenylethyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 113Benzyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 128 Cyclohexylmethyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 144 Methyl methylphenyl H H 2,6-dimethyl-4- H aminocarbonyl 180 Methyl methyl phenyl H H2,6-dimethyl-4- H (morpholin-4- ylcarbonyl) 182 Methyl methyl phenyl H H2,6-dimethyl-4- H ethylamino carbonyl 184 Methyl methyl phenyl H H2,6-dimethyl-4- H methylamino carbonyl 203 Methyl methyl phenyl H H4-amino- H carbonyl 206 Methyl methyl phenyl H H 2,6-dimethyl-4- Hhydroxy 208 H methyl phenyl H H 2,6-dimethyl-4- H hydroxy 210 Methylmethyl phenyl H H 4-hydroxy H 212 H methyl phenyl H H 4-hydroxy H 214Ethyl methyl phenyl H H 4-hydroxy H 217 Ethyl methyl phenyl H H2,6-dimethyl-4- H hydroxy 220 Benzyl methyl phenyl H H 2,6-dimethyl-4- Hhydroxy 221 Benzyl methyl phenyl H H 4-hydroxy H 222 Isopropyl methylphenyl H H 4-hydroxy H 223 Isopropyl methyl phenyl H H 2,6-dimethyl-4- Hhydroxy 228 3-Carboxy-phenyl methyl 4-chlorophenyl Me H 2,6-dimethyl-4-H methyl aminocarbonyl 276 3-Carboxy-phenyl methyl 4-chlorophenyl Me H4-amino- H carbonyl 278 3-Carboxy-4- methyl 4-chlorophenyl Me H2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 280 3-Methoxy-methyl phenyl H H 2,6-dimethyl-4- H carbonyl- aminocarbonyl 4-methoxy-phenylmethyl 281 3-Methoxy- methyl phenyl H H 4-amino- H carbonyl-carbonyl 4-methoxy- phenylmethyl 282 3-Carboxy-4- methyl phenyl H H2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 283 3-Carboxy-4-methyl phenyl H H 4-amino- H methoxy- carbonyl phenylmethyl 2943-Carboxy-4- methyl 4-chlorophenyl Me H 4-hydroxy H methoxy-phenylmethyl 314 6- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl-aminocarbonyl pyridin-2-ylmethyl 318 3-Carboxy-4- methyl 4-chlorophenylH H 4-amino- H methoxy- carbonyl phenylmethyl

Another embodiment is directed to compositions comprised of a compoundof Formula (Id):

wherein in one embodiment of this invention the variables are aspreviously defined. In another embodiment of the present invention L isoxygen and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependentlyselected from the group consisting of:

TABLE III Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b) 273 3-Carboxy-4- methylphenyl H H 4-amino- H methoxyphenyl carbonyl methyl

Exemplified compounds of the present invention include compounds ofFormula (Ie):

wherein in one embodiment of this invention the variables are aspreviously defined. In another embodiment of the present invention L isO and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependentlyselected from the group consisting of:

TABLE IV Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b) 284 3-Methoxy- methylphenyl H H 4-amino- H carbonyl- carbonyl 4-methoxy- phenylmethyl 2853-Carboxy-4- methyl phenyl H H 4-amino- H methoxy- carbonyl phenylmethyl

A further embodiment of the present invention includes representativecompounds shown in Table V:

TABLE V Cpd 4

6

8

12

18

20

75

227

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm. Sci., 1997 (January), 66, 1, 1). Other salts may, however, beuseful in the preparation of compounds according to this invention or oftheir pharmaceutically acceptable salts. Representative organic orinorganic acids include, but are not limited to, hydrochloric,hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diasteromers by standard techniques,such as the formation of stereoisomeric pairs by salt formation with anoptically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of stereoisomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.It is to be understood that all stereoisomers, racemic mixtures,diastereomers and enantiomers thereof are encompassed within the scopeof the present invention.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “phenylC₁-C₆ alkylamidoC₁-C₆alkyl”substituent refers to a group of the formula:

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

An “independently” selected substituent refers to a group ofsubstituents, wherein the substituents may be different. Therefore,designated numbers of carbon atoms (e.g. C₁₋₈) shall refer independentlyto the number of carbon atoms in an alkyl or cycloalkyl moiety or to thealkyl portion of a larger substituent in which alkyl appears as itsprefix root.

As used herein, unless otherwise noted, “alkyl” whether used alone or aspart of a substituent group refers to straight and branched carbonchains having 1 to 8 carbon atoms or any number within this range. Theterm “alkoxy” refers to an -Oalkyl substituent group, wherein alkyl isas defined supra. Similarly, the terms “alkenyl” and “alkynyl” refer tostraight and branched carbon chains having 2 to 8 carbon atoms or anynumber within this range, wherein an alkenyl chain has at least onedouble bond in the chain and an alkynyl chain has at least one triplebond in the chain. An alkyl and alkoxy chain may be substituted on acarbon atom. In substituent groups with multiple alkyl groups such as(C₁₋₆alkyl)₂amino- the C₁₋₆alkyl groups of the dialkylamino may be thesame or different.

The term “cycloalkyl” refers to saturated or partially unsaturated,moncyclic or polycyclic hydrocarbon rings of from 3 to 14 carbon atommembers. Examples of such rings include, and are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andadamantyl. Alternatively, the cycloalkyl ring may be fused to a benzenering (benzo fused cycloalkyl), a 5 or 6 membered heteroaryl ring(containing one of O, S or N and, optionally, one additional nitrogen)to form a heteroaryl fused cycloalkyl.

The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 7members in which 1 to 2 members are nitrogen, or a nonaromatic cyclicring of 5 to 7 members in which zero, one or two members are nitrogenand up to two members are oxygen or sulfur; wherein, optionally, thering contains zero to one unsaturated bonds, and, optionally, when thering is of 6 or 7 members, it contains up to two unsaturated bonds. Theterm “heterocyclyl” includes a 5 to 7 membered monocyclic heterocyclicring fused to a benzene ring (benzo fused heterocyclyl), a 5 or 6membered heteroaryl ring (containing one of O, S or N and, optionally,one additional nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenylring, a 5 to 7 membered heterocyclyl ring (of the same definition asabove but absent the option of a further fused ring) or fused with thecarbon of attachment of a cycloalkyl, cycloalkenyl or heterocyclyl ringto form a spiro moiety. For instant compounds of the invention, thecarbon atom ring members that form the heterocyclyl ring are fullysaturated. Other compounds of the invention may have a partiallysaturated heterocyclyl ring. The term “heterocyclyl” also includes a 5to 7 membered monocyclic heterocycle bridged to form bicyclic rings.Such compounds are not considered to be fully aromatic and are notreferred to as heteroaryl compounds. Examples of heterocyclyl groupsinclude, and are not limited to, pyrrolinyl (including 2H-pyrrole,2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl,imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl and piperazinyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6carbon members or to an unsaturated, aromatic polycyclic ring of from 10to 14 carbon members. Examples of such aryl rings include, and are notlimited to, phenyl, naphthalenyl or anthracenyl. Preferred aryl groupsfor the practice of this invention are phenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include nitrogen, oxygen orsulfur. In the case of 5 membered rings, the heteroaryl ring containsone member of nitrogen, oxygen or sulfur and, in addition, may containup to three additional nitrogens. In the case of 6 membered rings, theheteroaryl ring may contain from one to three nitrogen atoms. For thecase wherein the 6 membered ring has three nitrogens, at most twonitrogen atoms are adjacent. Optionally, the heteroaryl ring is fused toa benzene ring (benzo fused heteroaryl), a 5 or 6 membered heteroarylring (containing one of O, S or N and, optionally, one additionalnitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 memberedheterocyclo ring (as defined supra but absent the option of a furtherfused ring). Examples of heteroaryl groups include, and are not limitedto, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fusedheteroaryl groups include indolyl, isoindolyl, indolinyl, benzofuryl,benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolizinyl,quinolinyl, isoquinolinyl or quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group(e.g., benzyl, phenethyl). Similarly, the term “arylalkoxy” indicates analkoxy group substituted with an aryl group (e.g., benzyloxy).

The term “halogen” refers to fluorine, chlorine, bromine and iodine.Substituents that are substituted with multiple halogens are substitutedin a manner that provides compounds, which are stable.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) it shallbe interpreted as including those limitations given above for “alkyl”and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger substituent in which alkyl appears as itsprefix root. For alkyl, and alkoxy substituents the designated number ofcarbon atoms includes all of the independent member included in therange specified individually and all the combination of ranges within inthe range specified. For example C₁₋₆ alkyl would include methyl, ethyl,propyl, butyl, pentyl and hexyl individually as well as sub-combinationsthereof (e.g. C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅,etc.).

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

The novel compounds of the present invention are useful opioid receptormodulators. In particular, certain compounds are opioid receptoragonists useful in the treatment or amelioration of conditions such aspain and gastrointestinal disorders. Examples of pain intended to bewithin the scope of the present invention include, but are not limitedto, centrally mediated pain, peripherally mediated pain, structural orsoft tissue injury related pain, pain related to inflammation,progressive disease related pain, neuropathic pain and acute pain suchas caused by acute injury, trauma or surgery and chronic pain such ascaused by neuropathic pain conditions, diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, post-stroke painsyndromes or cluster or migraine headaches. Examples of gastrointestinaldisorders intended to be within the scope of this invention include, butare not limited to, diarrheic syndromes, motility disorders such asdiarrhea-predominant, or alternating irritable bowel syndrome, andvisceral pain and diarrhea associated with inflammatory bowel diseaseincluding ulcerative colitis and Crohn's disease.

Examples of gastrointestinal disorders where opioid receptor (“OR”)antagonists are useful include constipation-predominant irritable bowelsyndrome, post-operative ileus and constipation, including but notlimited to the constipation associated with treatment of chronic painwith opiates. Modulation of more than one opioid receptor subtype isalso useful as follows: a compound that is a mixed mu OR agonist anddelta OR antagonist could have antidiarrheal properties without beingprofoundly constipating. A compound that is a mixed mu OR agonist anddelta OR agonist are useful in cases of severe diarrhea that arerefractory to treatment with pure mu OR agonists, or has additionalutility in treating visceral pain associated with inflammation anddiarrhea.

Accordingly, a compound of the present invention may be administered byany conventional route of administration including, but not limited tooral, nasal, pulmonary, sublingual, ocular, transdermal, rectal, vaginaland parenteral (i.e. subcutaneous, intramuscular, intradermal,intravenous etc.). It is currently preferred that the compounds of thepresent invention be administered via modes of administration other thanpulmonary or parenteral administration. However, the preferred compoundsprovided in Table IV may be administered via pulmonary or parenteralmodes of administration.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

In preparing a pharmaceutical composition of the present invention inliquid dosage form for oral, topical and parenteral administration, anyof the usual pharmaceutical media or excipients may be employed. Thus,for liquid dosage forms, such as suspensions (i.e. colloids, emulsionsand dispersions) and solutions, suitable carriers and additives include,but are not limited to, pharmaceutically acceptable wetting agents,dispersants, flocculation agents, thickeners, pH control agents (i.e.buffers), osmotic agents, coloring agents, flavors, fragrances,preservatives (i.e. to control microbial growth, etc.) and a liquidvehicle may be employed. Not all of the components listed above will berequired for each liquid dosage form.

In solid oral preparations such as, for example, dry powders forreconstitution or inhalation, granules, capsules, caplets, gelcaps,pills and tablets (each including immediate release, timed release andsustained release formulations), suitable carriers and additives includebut are not limited to diluents, granulating agents, lubricants,binders, glidants, disintegrating agents and the like. Because of theirease of administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. If desired, tablets may be sugarcoated, gelatin coated, film coated or enteric coated by standardtechniques.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful and the like, anamount of the active ingredient necessary to deliver an effective doseas described above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01 mg/kg to about300 mg/kg (preferably from about 0.01 mg/kg to about 100 mg/kg; and,more preferably, from about 0.01 mg/kg to about 30 mg/kg) and may begiven at a dosage of from about 0.01 mg/kg/day to about 300 mg/kg/day(preferably from about 0.01 mg/kg/day to about 100 mg/kg/day and morepreferably from about 0.01 mg/kg/day to about 30 mg/kg/day). Preferably,the method for the treatment of conditions that may be mediated byopioid receptors described in the present invention using any of thecompounds as defined herein, the dosage form will contain apharmaceutically acceptable carrier containing between from about 0.01mg to about 100 mg; and, more preferably, from about 5 mg to about 50 mgof the compound, and may be constituted into any form suitable for themode of administration selected. The dosages, however, may be varieddepending upon the requirement of the subjects, the severity of thecondition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, dry powders for reconstitution or inhalation,granules, lozenges, sterile solutions or suspensions, metered aerosol orliquid sprays, drops, or suppositories for administration by oral,intranasal, sublingual, intraocular, transdermal, rectal, vaginal, drypowder inhaler or other inhalation or insufflation means.

For preparing solid pharmaceutical compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and gildants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable gildants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W.R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate, cellulose acetate trimetllitate), polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate and ethylacrylatecopolymers, methacrylate and methyl methacrylate copolymers and thelike. Sustained release tablets may also be made by film coating or wetgranulation using slightly soluble or insoluble substances in solution(which for a wet granulation acts as the binding agents) or low meltingsolids a molten form (which in a wet granulation may incorporate theactive ingredient). These materials include natural and syntheticpolymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and thelike), esters of fatty acids metallic soaps, and other acceptablematerials that can be used to granulate, coat, entrap or otherwise limitthe solubility of an active ingredient to achieve a prolonged orsustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever treatment of disordersthat may be mediated or ameliorated by opioid receptors for a subject inneed thereof.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.1 mg to about 7000 mg peradult human per day; most preferably the dose will be in the range offrom about 0.7 mg to about 2100 mg per adult human per day. For oraladministration, the compositions are preferably provided in the form oftablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the subjectto be treated. An effective amount of the drug is ordinarily supplied ata dosage level of from about 0.01 mg/kg to about 300 mg/kg of bodyweight per day. Preferably, the range is from about 0.01 mg/kg to about100 mg/kg of body weight per day; and, most preferably, from about 0.01mg/kg to about 30 mg/kg of body weight per day. Advantageously, acompound of the present invention may be administered in a single dailydose or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease condition. In addition, factors associatedwith the particular subject being treated, including subject age,weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level.

Representative IUPAC names for the compounds of the present inventionwere derived using the AutoNom version 2.1 nomenclature software programprovided by Beilstein Informationssysteme.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

-   BOC=tert-butoxycarbonyl-   BuLi=n-butyllithium-   CBZ=benzyloxycarbonyl-   Cpd or Cmpd=compound-   d=day/days-   DIPEA=diisopropylethylamine-   DPPF=1,1′-bis(diphenylphosphino)ferrocene-   DPPP=1,3-Bis(diphenylphosphino)propane-   EDCI or EDC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide    hydrochloride-   EtOAc=ethyl acetate-   EtOH=ethanol-   h=hour/hours-   HMDS=1,1,3,3-Hexamethyldisilazane-   HOBt/HOBT=hydroxybenzothiazole-   M=molar-   MeCN=acetonitrile-   MeOH=methanol-   min=minutes-   PyBOP=Benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium    hexafluorophosphate-   rt/RT=room temperature-   TFA=trifluoroacetic acid-   OTf=triflate-   Ts=tosyl

Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

The following schemes describe general synthetic methods wherebyintermediate and target compounds of the present invention may beprepared. Additional representative compounds and stereoisomers, racemicmixtures, diasteromers and enantiomers thereof can be synthesized usingthe intermediates prepared in accordance to the general schemes andother materials, compounds and reagents known to those skilled in theart. All such compounds, stereoisomers, racemic mixtures, diasteromersand enantiomers thereof are intended to be encompassed within the scopeof the present invention.

Certain intermediates and compounds of the present invention may beprepared according to the process outlined in Scheme A below.

A carboxylic acid of the formula A-1, available either commercially orprepared by reported protocols in the scientific literature, may becoupled to an α-aminoketone using standard peptide coupling conditionswith a coupling agent such as EDCI and an additive such as HOBt toprovide a compound of formula A-2. Compound A-2 may be condensed with anamine of the formula H₂N—R₅ or ammonium acetate and cyclized uponheating in acetic acid to a compound of formula A-4.

The protecting group of compound A-4 may be removed using conditionsknown to those skilled in the art that are appropriate for theparticular protecting group to afford a compound of the formula A-6. Forinstance, hydrogenation in the presence of a palladium catalyst is onemethod for the removal of a CBZ protecting group, whereas treatment withan acid such as TFA is effective for a BOC group deprotection.

A compound of formula A-6 may be substituted using reductive aminationwith an appropriately substituted aldehyde or ketone in the presence ofa hydride source, such as sodium borohydride or sodiumtriacetoxyborohydride, provide compounds of formula A-10.

Alternatively, a compound of formula A-3 may be condensed with adicarbonyl compound of the formula R₃(C═O)₂R₃ and an amine of theformula H₂N—R₅ upon heating in acetic acid to afford a compound of theformula A-4. When compound A-3 is protected with a BOC group, aby-product of formula A-5 may be produced. Compounds of formula A-4 orA-5 may be treated with a hydride source such as lithium aluminumhydride to give certain compounds of formula A-10.

Similarly, a compound of formula A-7 may be coupled to an α-aminoketoneas described above for compounds of formula A-1 to yield thecorresponding compounds of formula A-8. A compound of formula A-8 maythen be cyclized in the presence of an amine of formula H₂N—R₅ orammonium acetate and subsequently deprotected as described above toarrive at compounds of formula A-10.

Certain compounds of the present invention may be prepared according tothe process outlined in Scheme B below.

More specifically, a compound of formula B-1 (wherein the imidazolenitrogen is substituted with R⁵, as defined herein, or R^(5a), anitrogen protecting group such as SEM, MOM, or the like) may bedeprotonated with an organometallic base such as n-butyllithium and thentreated with a suitably substituted amide to yield a compound of formulaB-2.

Compound B-2 may be brominated to yield a mixture of regioisomers offormula B-3. A compound of formula B-3 may be further elaborated via areductive amination with an amine of the formula H₂N—R¹ in the presenceof a hydride source as described in Scheme A to afford a compound offormula B-4.

The amine of a compound of formula B-4 may be coupled with a suitablecarboxylic acid under standard peptide coupling conditions with acoupling agent such as EDCI and an additive such as HOBt to yieldcompounds of formula B-5.

Certain R³ substituents of the present invention in which a carbon atomis the point of attachment may be introduced into a compound of formulaB-5 through a transition metal-catalyzed cross coupling reaction toafford compounds of formula B-6. Suitable palladium catalysts includepalladium tetrakis triphenylphosphine and the like. Suitable Lewis acidsfor the reaction include boronic acids and the like. Compounds protectedwith R^(5a) may be deprotected under acidic conditions to yieldcompounds of formula B-7.

In a similar manner, an intermediate B-2 when optionally protected withR^(5a) may be reductively alkylated using methods described above togive a compound of formula B-8, followed by removal of protecting groupR^(5a) using conditions described herein to yield a compound of formulaB-9.

One skilled in the art will recognize that substituent L (depicted as Oin the formulae of Scheme B) may be further elaborated to S or N(R^(d))of the present invention using conventional, known chemical methods.

Certain compounds of the present invention may be prepared according tothe process outlined in Scheme C below.

More specifically, a compound of formula A-10, B-8, or B-9 may beelaborated to a compound of formula C-2 through coupling with a suitablecarboxylic acid under standard peptide coupling conditions as describedabove. One skilled in the art will recognize that substituent L in acompound of formula C-2 (depicted as O) may be converted to S orN(R^(d)) of the present invention using conventional, known chemicalmethods.

Suitably substituted carboxylic acids of the present invention mayeither be commercially available or prepared by reported protocols inthe scientific literature. Several chemical routes for preparing certaincompounds of formula C-1 are outlined below in Schemes D and E.

Specifically, a compound of formula D-1 may be treated withtrifluoromethanesulfonic anhydride to afford the triflate compound offormula D-2. A compound of formula D-2 may be converted to a compound offormula D-4 by a variety chemical routes which utilize conventionalchemical methods known to those skilled in the art. For example, thebromo group of a compound of formula D-2 may undergo a carboxylationreaction via an initial carbonylation under a carbon monoxide atmospherein the presence of an appropriate palladium catalyst and DPPF, followedby an aqueous basic workup to afford a compound of formula D-3.Subsequently, the carboxyl group may be converted to a substituent ofR^(41a) of formula D-4 using standard peptide coupling conditions.Alternatively, a compound of formula D-4 may be directly prepared via acarbonylation of compound of formula D-2, followed by treatment withHMDS, or a primary or secondary amine.

The compound of formula D-5, known or prepared by known methods, may betreated with EDC in the presence of copper (I) chloride to afford thecorresponding alkene of formula D6. A compound of formula D-6 may thenundergo a Heck reaction with a compound of formula D-4 in the presenceof an appropriate palladium catalyst and phosphino ligand to afford acompound of formula D7. Subsequent hydrogenation of the alkenylsubstituent using standard hydrogen reduction methods affords a compoundof formula D-8.

Scheme E demonstrates an alternative method for preparing intermediateD-7 of the present invention. A compound of formula E-1 may beelaborated to a compound of formula E-4 using the appropriately adaptedsynthetic steps described in Scheme D. One skilled in the art willrecognize that this transformation may be achieved by manipulation ofthe reaction sequence. A compound of formula E-4 may be converted to itscorresponding nitrile via an aromatic nucleophilic displacement reactionwith cyanide anion. One skilled in the art will recognize that a nitrilesubstituent is a viable synthon for a substituent of R^(41a).

A compound of formula E-4 may participate in a Horner-Wadsworth-Emmonsreaction with a compound of formula E-7 in the presence of anorganometallic base such as n-butyllithiium to afford a compound offormula D-7. This intermediate may be further elaborated as described inScheme D, herein.

Certain compounds of the present invention may be prepared according tothe process outlined in Scheme F below.

More specifically, a compound of formula F-1, wherein R¹¹ is analkoxycarbonyl as defined above, may be saponified to its correspondingacid, a compound of formula F-2.

A compound of formula F-3 wherein R¹¹ is a cyano substituent may beelaborated to its corresponding aminocarbonyl, compound F-4 by treatmentwith hydrogen peroxide in the presence of hydroxide anion. Similarly,when R³ is a cyano-substituted aryl ring, it may be treated as describedabove to form an aminocarbonyl-substituted aryl ring.

Certain substitutents of R¹¹ may be installed via a palladium catalyzedcoupling reaction with an X-substituted precursor. For example, acompound of formula F-5 wherein X is iodide, bromide, tosylate,triflate, or the like may be treated with Zn(CN)₂ in the presence ofpalladium tetrakis triphenylphosphine to give a compound of formula F-6wherein R¹¹ is cyano.

Treatment of a compound of formula F-5 with Pd(OAc)₂ and a ligand suchas 1,1-bis(diphenylphosphino) ferrocene under a carbon monoxideatmosphere provides a compound of formula F-6 wherein R¹¹ is a carboxysubstituent.

The palladium catalyzed couplings described above may also be used toinstall cyano, carboxy, and alkoxycarbonyl substituents onto an arylring at R³.

SPECIFIC EXAMPLES

Specific compounds which are representative of this invention wereprepared as per the following examples and reaction sequences; theexamples and the diagrams depicting the reaction sequences are offeredby way of illustration, to aid in the understanding of the invention andshould not be construed to limit in any way the invention set forth inthe claims which follow thereafter. The instant compounds may also beused as intermediates in subsequent examples to produce additionalcompounds of the present invention. No attempt has been made to optimizethe yields obtained in any of the reactions. One skilled in the artwould know how to increase such yields through routine variations inreaction times, temperatures, solvents and/or reagents.

Reagents were purchased from commercial sources. Nuclear magneticresonance (NMR) spectra for hydrogen atoms were measured in theindicated solvent with (TMS) as the internal standard on a BrukerBiospin, Inc. DPX-300 (300 MHz) spectrometer. The values are expressedin parts per million down field from TMS. The mass spectra (MS) weredetermined on a Micromass Platform LC spectrometer or an Agilent LCspectrometer using electrospray techniques. Microwave acceleratedreactions were performed using either a CEM Discover or a PersonalChemistry Smith Synthesizer microwave instrument. Stereoisomericcompounds may be characterized as racemic mixtures or as separatediastereomers and enantiomers thereof using X-ray crystallography andother methods known to one skilled in the art. Unless otherwise noted,the materials used in the examples were obtained from readily availablecommercial suppliers or synthesized by standard methods known to oneskilled in the art of chemical synthesis. The substituent groups, whichvary between examples, are hydrogen unless otherwise noted.

Example 12-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-N-isopropyl-N-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-propionamide

A. [1-(2-Oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester

To a solution of commercially available N-α-CBZ-L-alanine (2.11 g, 9.5mmol) in dichloromethane (50 mL) was added 2-aminoacetophenonehydrochloride (1.62 g, 9.5 mmol). The resulting solution was cooled to0° C. and N-methylmorpholine (1.15 g, 11 mmol), 1-hydroxybenzotriazole(2.55 g, 18.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (2.35 g, 12.3 mmol) in that order were added under anArgon atmosphere. The reaction mixture was warmed to room temperatureand stirred overnight. The reaction was quenched by addition ofsaturated aqueous NaHCO₃ solution; the separated organic phase waswashed with 2N citric acid, saturated NaHCO₃ solution and brine, thendried over MgSO₄ overnight. After filtration and concentration, theresidue was purified by column chromatography on silica gel (eluent,EtOAc:hexane-1:1) to give the pure product:[1-(2-oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester(2.68 g, 83%). ¹H NMR (300 MHz, CDCl₃): δ 1.46 (3H, d), 4.39 (1H, m),4.75 (2H, d), 5.13 (2H, d), 5.40 (1H, m), 7.03 (1H, m), 7.36 (5H, m),7.50 (2H, m), 7.63 (1H, m), 7.97 (2H, m). MS (ES⁺): 341.1 (100%).

B. [1-(4-Phenyl-1H-imidazol-2-yl)-ethyl]-carbamic acid benzyl ester

To a suspension of [1-(2-oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamicacid benzyl ester (2.60 g, 7.64 mmol) in xylene (60 mL) was added NH₄OAc(10.3 g, 134 mmol) and HOAc (5 mL). The resulting mixture was heated atreflux for 7 h. After being cooled to room temperature, brine was addedand the mixture was separated. The aqueous phase was extracted withEtOAc, and the combined organic phases were dried over Na₂SO₄ overnight.After filtration and concentration, the residue was purified by columnchromatography on silica gel (eluent, EtOAc:hexane-1:1) to give thetitle compound (2.33 g, 95%). ¹H NMR (300 MHz, CDCl₃): δ 1.65 (3H, d),5.06 (1H, m), 5.14 (2H, q), 5.94 (1H, d), 7.32 (10H, m), 7.59 (2H, d).MS (ES⁺): 322.2 (100%).

C. 1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine

To a solution of [1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamic acidbenzyl ester (1.5 g, 4.67 mmol) in methanol (25 mL) was added 10%palladium on carbon (0.16 g). The mixture was shaken in a hydrogenationapparatus at rt under a hydrogen atmosphere (10 psi) for 8 h. Filtrationfollowed by evaporation to dryness under reduced pressure gave the crudeproduct 1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.88 g, 100%). ¹H NMR(300 MHz, CDCl₃): δ 1.53 (3H, d), 4.33 (1H, q), 7.23 (3H, m), 7.37 (2H,m), 7.67 (2H, m). MS (ES⁺): 188.1 (38%).

D. Isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine

1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.20 g, 1.07 mmol) and acetone(0.062 g, 1.07 mmol) were mixed in 1,2-dichloroethane (4 mL), followedby the addition of NaBH(OAc)₃ (0.34 g, 1.61 mmol). The resulting mixturewas stirred at rt for 3 h. The reaction was quenched with saturatedNaHCO₃ solution. The mixture was extracted with EtOAc and the combinedextracts were dried over Na₂SO₄. Filtration followed by evaporation todryness under reduced pressure gave the crudeisopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.23 g, 100%)which was used for the next reaction without further purification. ¹HNMR (300 MHz, CDCl₃): δ 1.10 (3H, d), 1.18 (3H, d), 1.57 (3H, d), 2.86(1H, m), 4.32 (1H, m), 7.24 (2H, m), 7.36 (2H, m), 7.69 (2H, m). MS(ES⁺): 230.2 (100%).

E.(2-(4-Hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]carbamoyl}-ethyl)-carbamicacid tert-butyl ester

Into a solution of2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionicacid (0.18 g, 0.6 mmol) in DMF (7 mL) was addedisopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.11 g, 0.5mmol), 1-hydroxybenzotriazole (0.22 g, 1.6 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.12 g,0.6 mmol). The resulting mixture was stirred under an Argon atmosphereat rt overnight. The reaction mixture was extracted with EtOAc and thecombined organic extracts were washed sequentially with saturatedaqueous NaHCO₃ solution, 1N HCl, saturated aqueous NaHCO₃ solution, andbrine. The organic phase was then dried over MgSO₄, filtered, and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography (eluent: EtOAc) to affordthe product(2-(4-hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamicacid tert-butyl ester (0.13 g, 50%). MS (ES⁺): 521.5 (100%).

F.2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-N-isopropyl-N-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-propionamide

A solution of(2-(4-hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamicacid tert-butyl ester (0.13 g, 0.25 mmol) in trifluoroacetic acid (5 mL)was stirred at rt for 2 h. Upon removal of the solvents, the residue waspurified by preparative LC and lyophilized to give the TFA salt of thetitle compound as a white powder (0.042 g). ¹H NMR (300 MHz, CDCl₃): δ0.48 (3H, d), 1.17 (3H, d), 1.76 (3H, d), 2.28 (6H, s), 3.19 (2H, m),3.74 (1H, m), 4.70 (1H, m), 4.82 (1H, q), 6.56 (2H, s), 7.45 (4H, m),7.74 (2H, m). MS (ES⁺): 421.2 (100%).

Example 2 Methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]amineand Ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine

A. [2-Methyl-1-(2-oxo-2-phenyl-ethylcarbamoyl)-propyl]carbamic acidtert-butyl ester

Compound 2a was prepared according to Example 1 using the appropriatereagents, starting materials and methods known to those skilled in theart.

B. [2-Methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]-carbamic acidtert-butyl ester

Following the procedure described in Example 1 for the conversion ofCompound 1a to Compound 1b, and using the appropriate reagents andmethods known to those skilled in the art,[2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]-carbamic acidtert-butyl ester, Cpd 2b, was prepared.

Subsequent to workup, the crude product mixture was subjected to flashsilica gel chromatography (eluents: CH₂Cl₂, followed by 4:1 CH₂Cl₂/Et₂O,then EtOAc). Processing of the fractions afforded 1.08 g (27%) ofrecovered [2-methyl-1-(2-oxo-2-phenyl-ethylcarbamoyl)-propyl]-carbamicacid tert-butyl ester (Cpd 2a), 1.89 g (50%) of[2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]-carbamic acidtert-butyl ester (Cpd 2b), and 0.60 g of a mixture ofN-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-acetamide (Cpd 2c) andacetamide.

Cpd 2c was purified by dissolving it in hot CH₃CN and cooling to 0° C.Collection of the precipitate by suction filtration afforded 0.21 g (7%)of N-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-acetamide, Cpd 2c,as a white powder (HPLC: 100% @ 254 nm and 214 nm). ¹H NMR (300 MHz,CDCl₃): δ 7.63 (2H, br s), 7.33 (2H, t, J=7.5 Hz), 7.25-7.18 (2H, m),4.78 (1H, br s), 2.35 (1H, br m), 2.02 (3H, s), 1.03 (3H, d, J=6.7 Hz),0.87 (3H, d, J=6.7 Hz); MS (ES⁺) (relative intensity): 258.3 (100)(M+1).

C. Methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]amine

A solution of [2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]carbamicacid tert-butyl ester (0.095 g, 0.30 mmol) in THF (2.0 mL) was addeddropwise over 10 min to a refluxing 1.0 M solution of LiAlH₄ in THF (3.0mL). The reaction was maintained at reflux for 2 h, cooled to roomtemperature, and quenched by sequential treatment with 0.11 mL of coldwater (5° C.), 0.11 mL of 15% NaOH in aqueous solution, and 0.33 mL ofcold water (5° C.). The resultant solid was removed by suctionfiltration and the filtrate (pH 8-9) was extracted three times withEtOAc. The combined organic fractions were dried over MgSO₄, filtered,and concentrated to afford 0.58 g (84%) ofmethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine as a lightyellow oil (HPLC: 97% @ 254 nm and 214 nm). ¹H NMR (300 MHz, CDCl₃): δ7.69 (2H, d, J=7.4 Hz), 7.36 (2H, t, J=7.6 Hz), 7.26 (1H, s), 7.25-7.20(1H, m), 3.62 (1H, d, J=6.3 Hz), 2.35 (3H, s), 2.06 (1H, m), 0.99 (3H,d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz); MS (ES⁺) (relative intensity):230.2 (100) (M+1).

D. Ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine

A solution ofN-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-acetamide (0.077 g,0.30 mmol) in THF (2.0 mL) was added dropwise over 10 min to a refluxing1.0 M solution of LiAlH₄ in THF (3.0 mL). The reaction was maintained atreflux for 11 h, cooled to rt, and quenched by sequential treatment with0.11 mL of cold water (5° C.), 0.11 mL of 15% NaOH in aqueous solution,and 0.33 mL of cold water (5° C.). The resultant solid was removed bysuction filtration and the filtrate (pH 8-9) was extracted three timeswith EtOAc. The combined organic fractions were dried over MgSO₄,filtered, and concentrated to afford 0.069 g of a 5:1 mixture(determined by ¹H NMR) ofethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine andrecovered Cpd 2c as a colorless oil (HPLC: peaks overlap). ¹H NMR (300MHz, CDCl₃): δ 7.67 (2H, br s), 7.35 (2H, t, J=7.6 Hz), 7.26-7.17 (2H,m), 3.72 (1H, d, J=6.0 Hz), 2.56 (2H, dq, J=13.0, 7.1 Hz), 2.05 (1H, m),1.08 (3H, t, J=7.1 Hz), 0.97 (3H, d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz);MS (ES⁺) (relative intensity): 244.2 (100) (M+1). This sample was ofsufficient quality to use in the next reaction without furtherpurification.

Methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine andethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine may besubstituted for Cpd 1d of Example 1 and elaborated to compounds of thepresent invention with the appropriate reagents, starting materials andpurification methods known to those skilled in the art.

Example 3(3,4-Dimethoxy-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine

A solution of 1-(4-phenyl-1H-imidazol-2-yl)-ethylamine (0.061 g, 0.33mmol) of Example 1, and 0.55 g (0.33 mmol) of 3,4-dimethoxybenzaldehydein 5 mL of anhydrous methanol was stirred at room temperature for 1 hand then cooled to about 0-10° C. in an ice bath for 1 h. The reactionwas treated carefully with 0.019 g (0.49 mmol) of sodium borohydride inone portion and maintained at about 0-10° C. for 21 h. Cold 2M aqueousHCl was added dropwise (30 drops), the mixture was stirred for 5 min,and then partially concentrated in vacuo unheated. The residual materialwas taken up in EtOAc to yield a suspension that was treated with 5 mLof cold 3M aqueous NaOH and stirred vigorously until clear. The phaseswere separated and the aqueous layer was extracted three timesadditional with EtOAc. The combined extracts were dried over MgSO₄,filtered, and concentrated to afford 0.11 g of(3,4-dimethoxy-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine as alight yellow oil (HPLC: 87% @ 254 nm and 66% @ 214 nm). MS (ES⁺)(relative intensity): 338.1 (100) (M+1). This sample was of sufficientquality to use in the next reaction without further purification. Thetitle compound may be substituted for Cpd 1d of Example 1 and elaboratedto compounds of the present invention with the appropriate reagents,starting materials and purification methods known to those skilled inthe art.

Example 4 1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-ethylamine

A. {1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]ethyl}-carbamic acidtert-butyl ester

A mixture of ammonium acetate (19.3 g, 250 mmol) and glacial HOAc (35mL) was stirred mechanically and heated to about 100° C. to give acolorless solution in 5-10 min. After cooling to rt, a solid mixture ofN-t-BOC-L-Alaninal (commercially available from Aldrich) and4-fluorophenyl glyoxal hydrate was added in portions while stirring togive a yellow mixture. The resulting mixture was heated at 100° C. forapproximately 2 h before cooling to rt. The mixture was cooled to 0-5°C., then basified by dropwise addition of conc. NH₄OH (25 mL), H₂O (25mL), and EtOAc (40 mL), and additional conc. NH₄OH (50 mL) to render themixture alkaline. The phases were separated and the aqueous phase wasre-extracted with EtOAc. The combined organic phases were filteredthrough dicalite to remove an orange solid and were washed withsaturated aqueous NaCl. The organic phase was then dried over MgSO₄,filtered, and concentrated under reduced pressure to give 4.27 g of anorange-brown residue. The residue was dissolved in a solution of MeCN(22 mL) and DMSO (3 mL) then purified by preparative HPLC on a Kromasil10u C18 250×50 mm column, eluting with a 35:65 MeCN:H₂O gradient. Thepure fractions were combined and lyophilized to give 1.77 g of theproduct as a yellow-white powder (42%; TFA salt). MS: m/z 306.1 (MH⁺).

B. 1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-ethylamine

{1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-ethyl}-carbamic acidtert-butyl ester may be BOC-deprotected using the procedure described inExample 1 for the conversion of Cpd 1e to Cpd 1f. Upon completion of theBOC-deprotection, the resulting amine may be substituted for Cpd 1c ofExample 1 and elaborated to compounds of the present invention with theappropriate reagents, starting materials and purification methods knownto those skilled in the art.

Example 5Isopropyl-[4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-amine(mixture of regioisomers)

A. Cpd 5a Regioisomers

Into a cooled solution of4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (Tet. Lett.1986, 27(35), 4095-8) (7.70 g, 28.1 mmol) in dry THF (60 mL) was addedn-butyllithium (2.5 M in hexane, 22.5 mL, 56.2 mmol) at −78° C. underN₂. The resulting mixture was stirred at −78° C. for 1 h, followed bythe addition of DMF (4.35 mL, 56.2 mmol). After being stirred at −78° C.for an additional hour, the reaction was warmed to room temperature andstirred overnight. The reaction was quenched by the addition ofsaturated aqueous NaHCO₃ solution and extracted with EtOAc. The combinedorganic extracts were dried over Na₂SO₄. After filtration andevaporation, the residue was purified by flash column chromatography(eluent: EtOAc:hexane, 1:9) to give4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde(5.11 g, 60%) as a mixture of regioisomers. ¹H NMR (300 MHz, CDCl₃): δ0.00 (9H, s), 2.98 (2H, t), 3.62 (2H, t), 5.83 (2H, s), 7.36 (1H, m),7.44 (2H, m), 7.65 (1H, s), 7.86 (2H, m). MS (ES⁺): 303.0 (42%).

B. Cpd 5b Regioisomers

Isopropylamine (0.18 g, 3 mmol) and a regioisomeric mixture of4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde(0.91 g, 3 mmol) were mixed in 1,2-dichloroethane (10 mL), followed byaddition of sodium triacetoxyborohydride (0.95 g, 4.5 mmol). Theresulting mixture was stirred at room temperature for 5 h. The reactionwas quenched with saturated aqueous NaHCO₃ solution. The resultantmixture was extracted with EtOAc and the combined organic phases weredried over Na₂SO₄. After filtration and concentration, the residue waspurified by flash column chromatography (eluent: CH₂Cl₂:CH₃OH, 7:3) togiveisopropyl-[4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-amine(0.70 g, 68%) as a mixture of regioisomers. ¹H NMR (300 MHz, CDCl₃): δ0.00 (9H, s), 0.94 (2H, t), 1.11 (6H, d), 2.89 (1H, m), 3.56 (2H, t),3.94 (2H, s), 5.39 (2H, s), 7.25 (2H, m), 7.37 (2H, m), 7.76 (2H, d). MS(ES⁺): 346.6 (75%).

Compound 5b may be substituted for Cpd 1d of Example 1 and elaborated tocompounds of the present invention with the appropriate reagents,starting materials and purification methods known to those skilled inthe art.

Example 62-Amino-3-(4-hydroxy-phenyl)-N-isopropyl-N-(5-methyl-4-phenyl-1H-imidazol-2-ylmethyl)-propionamideTrifluoroacetate (1:2)

A. Cpd 6a Regioisomers

Bromine (1.17 mL, 22.76 mmol) was added slowly to an ice cooledregioisomeric mixture of4(5)-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde(5.47 g, 22.76 mmol; JOC, 1986, 51(10), 1891-4) in CHCl₃ (75 mL). Thereaction was warmed to rt after 1.5 h, and then was stirred anadditional 1 h. The reaction mixture was then extracted with saturatedaqueous NaHCO₃, and the organic phase was then dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give 7.46 g ofcrude material. This material was vacuum distilled (bp 127-135° C.; 1 mmHg) to yield 3.16 g (43%) of a regioisomeric mixture, Cpd 6a, as ayellow liquid, which was used without further purification. ¹H NMR(CDCl₃) δ 0 (s, 9H), 0.9-1.0 (t, 2H), 2.35 (s, 3H), 3.5-3.6 (t, 2H), 5.8(s, 2H), 9.75 (s, 1H).

B. Cpd 6b Regioisomers

Isopropyl amine (0.30 g, 5 mmol) in 1,2-dichloroethane (2 mL) was addedto a 5° C. solution of regioisomers Cpd 6a (0.96 g, 3 mmol) in1,2-dichloroethane (70 mL). After stirring for 5 min, sodiumtriacetoxyborohydride (1.80 g, 8.5 mmol) was added neat to the reactionmixture. The mixture was gradually warmed to rt and stirred for 24 h. Atthis time, an additional portion of sodium triacetoxyborohydride (0.60g, 2.8 mmol) was added and the reaction was stirred an additional 16 h.The reaction was then cooled to approximately 10° C. and treated whilestirring with saturated aqueous NaHCO₃. After stirring for 15 min, thelayers were separated and the organic phase was dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give 1.20 g (T.W.1.09 g) of a regioisomeric mixture, Cpd 6b, as a yellow oil which wasused directly without further purification.

C. Cpd 6c Regioisomers

Isobutyl chloroformate (0.43 g, 3.15 mmol) was added neat to a 0° C.solution containing2-tert-butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid (1.21g, 3.6 mmol; Advanced Chem Tech), N-methylmorpholine (362 μL, 3.3 mmol),and CH₂Cl₂ (60 mL). After stirring 1.5 h, Cpd 6b (1.09 g, 3 mmol) wasadded to the reaction mixture. The reaction mixture was then warmed toroom temperature and stirred for 16 h. The reaction mixture was thenadsorbed on silica gel, and flash chromatographed on a silica gel columneluting with 25% ethyl acetate/hexane. The desired fractions werecombined and concentrated under reduced pressure to give 715 mg (35%) ofregioisomers of Cpd 6c as a clear oil (TLC: 25% EtOAc/hexane R_(f)=0.3,homogeneous; HPLC: 100% at 254 and 214 nm, 7.51 min).

D. Cpd 6d Regioisomers

To the regioisomers of Cpd 6c (90 mg, 0.132 mmol) in 1,2-dimethoxyethane(2 mL) was added phenyl boronic acid (32.2 mg, 0.26 mmol) followed by 2MNa₂CO₃(aq) (0.53 mL, 1.06 mmol). The resulting mixture was degassed withN₂ for 5 min and then palladium tetrakis triphenylphosphine (53 mg,0.046 mmol) was added neat. The reaction vessel was capped and warmed to80° C. for 14 h with rapid stirring. After cooling to room temperaturethe mixture was dried over MgSO₄, filtered through dicalite, andconcentrated under a stream of N₂. The residue was dissolved in a smallamount of EtOAc and flash chromatographed on a silica gel column(Eluent: 5%-25% EtOAc/hexane). The desired fractions were concentratedunder reduced pressure to yield 55 mg (61%) as regioisomeric mixture ofCpd 6d, which was used without further purification (TLC: 25%EtOAc/hexane R_(f)=0.3; HPLC: 100% at 254 nm; 88% at 214 nm, 6.50 min).

E.2-Amino-3-(4-hydroxy-phenyl)-N-isopropyl-N-(5-methyl-4-phenyl-1H-imidazol-2-ylmethyl)-propionamideTrifluoroacetate (1:2)

Trifluoroacetic acid (1 mL) was added to the Cpd 6d regioisomers (55 mg,0.081 mmol) at room temperature. After 6 h, the excess TFA was removedunder a stream of N₂. The residue was dissolved in a small amount ofacetonitrile and purified by preparative HPLC on a YMC C18 100×20 mmcolumn. The purest fractions were combined and lyophilized to give 37 mg(74%) of the title compound as a white lyophil (TLC: 5:1 CHCl₃:MeOHR_(f)=0.55, homogeneous; HPLC: 100% at 214 nm; HPLC/MS: m/z 393 (MH⁺)).¹H NMR (MeOH-d₄) δ 0.85-0.9 (d, 3H), 1.2-1.25 (d, 3H), 2.45 (s, 3H),3.05-3.1 (t, 2H), 4.0-4.15 (m, 1H), 4.55-4.6 (d, 1H), 4.7-4.85 (m, 2H),6.65-6.7 (d, 2H), 6.95-7.0 (d, 2H), 7.45-7.6 (m, 5H).

Example 7 (3,4-Dichloro-benzyl)-(4-phenyl-1H-imidazol-2-ylmethyl)-amineTrifluoroacetate (1:2)

Using the procedure described in Example 5 and substituting3,4-dichloro-benzylamine for isopropylamine,(3,4-dichloro-benzyl)-[4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-aminewas prepared as a pair of regioisomers. A sample (95 mg, 0.21 mmol) ofthis compound was dissolved in TFA (3 mL) at room temperature. After 2 hthe mixture was concentrated under a stream of nitrogen. The residue waspurified by reverse phase HPLC, the purest fractions were combined andlyophilized to yield desired product(3,4-dichloro-benzyl)-(4-phenyl-1H-imidazol-2-ylmethyl)-amine as an offwhite lyophil.

Following the procedure described in Example 1, substituting(3,4-dichloro-benzyl)-(4(5)-phenyl-1H-imidazol-2-ylmethyl)-amine for Cpd1d, compounds of the present invention may be synthesized with theappropriate reagents, starting materials, and purification methods knownto those skilled in the art.

Example 8(S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionicacid methyl ester

A.(S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionicacid methyl ester

Into a cool solution of Boc-L-(2,6-diMe)Tyr-OMe (7.0 g, 21.6 mmol;Sources: Chiramer or RSP AminoAcidAnalogues) andN-phenyltrifluoromethanesulfonimide (7.9 g, 22.0 mmol) indichloromethane (60 mL) was added triethylamine (3.25 mL, 23.3 mmol).The resulting solution was stirred at 0° C. for 1 h and slowly warmed tort. Upon completion, the reaction was quenched by addition of water. Theseparated organic phase was washed with 1N NaOH aqueous solution, waterand dried over Na₂SO₄ overnight. After filtration and evaporation, theresidue was purified by flash column chromatography (eluent:EtOAc-hexane: 3:7) to give the desired product (9.74 g, 99%) as a clearoil; ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.06 (2H, d,J=7.7 Hz), 3.64 (3H, s), 4.51-4.59 (1H, m), 5.12 (1H, d, J=8.5 Hz), 6.92(2H, s); MS (ES+) (relative intensity): 355.8 (100) (M−Boc)⁺.

B.(S)-4-(2-tert-Butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoicacid

To a suspension of(S)-2-tert-butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionicacid methyl ester (9.68 g, 21.3 mmol), K₂CO₃ (14.1 g, 0.102 mol),Pd(OAc)₂ (0.48 g, 2.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene(2.56 g, 4.47 mmol) in DMF (48 mL) was bubbled in gaseous CO for 15 min.The mixture was heated to 60° C. for 8 h with a CO balloon. The coolmixture was partitioned between NaHCO₃ and EtOAc, and filtered. Theaqueous layer was separated, acidified with 10% citric acid aqueoussolution, extracted with EtOAc, and finally dried over Na₂SO₄.Filtration and concentration of the filtrate resulted in a residue. Theresidue was recrystallized from EtOAc-hexanes to afford the desiredproduct (7.05 g, 94%); 1H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.42(6H, s), 3.14 (2H, J=7.4 Hz), 3.65 (3H, s), 4.57-4.59 (1H, m), 5.14 (1H,d, J=8.6 Hz), 7.75 (2H, s); MS (ES+) (relative intensity): 251.9 (100)(M−Boc)⁺.

C.(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionicacid methyl ester

Into a stirring solution of(S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoicacid (3.00 g, 8.54 mmol), PyBOP (6.68 g, 12.8 mmol) and HOBt (1.74 g,12.8 mmol) in DMF (36 mL) was added DIPEA (5.96 mL, 34.2 mmol) and NH₄Cl(0.92 g, 17.1 mmol). The resulting mixture was stirred at rt for 40 minbefore being partitioned between aqueous NH₄Cl solution and EtOAc. Theseparated organic phase was washed sequentially with 2N citric acidaqueous solution, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄ overnight. After filtration and concentration, theresidue was purified by flash column chromatography (eluent: EtOAc) togive the product. (3.00 g, 100%); ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H,s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m),5.12 (1H, d, J=8.7 Hz), 5.65 (1H, br s), 6.09 (1H, br s), 7.46 (2H, s);MS (ES+) (relative intensity): 250.9 (100) (M−Boc)⁺.

D.(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionicacid

Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) andstirred at 0° C. Upon consumption of the starting materials, the organicsolvents were removed and the aqueous phase was neutralized with cooled1N HCl at 0° C., and extracted with EtOAc, and dried over Na₂SO₄overnight. Filtration and evaporation to dryness led to the title acid(S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionicacid (2.51 g, 87%); ¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (9H, s), 2.32 (6H,s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz),4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M−Boc)⁺.

Example 95-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid

A.2-Methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoicacid methyl ester

Using the procedures described for Example 3, substituting5-formyl-2-methoxy-benzoic acid methyl ester (WO 02/22612) for3,4-dimethoxybenzaldehyde,2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoicacid methyl ester was prepared.

B.5-({[2-tert-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}methyl)-2-methoxy-benzoicacid methyl ester

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e,substituting2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoicacid methyl ester for Cpd 1d and substituting2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionicacid of Example 8 for2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionicacid, Cpd 9a was prepared.

C.5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid

5-({[2-tert-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid methyl ester was dissolved in an ice-chilled (0-10° C.), mixedsolvent system of THF (10 mL) and MeOH (5 mL). A LiOH.H₂O/watersuspension (2.48 M; 3.77 mL) was added dropwise, then the reaction wasallowed to warm to room temperature and stirred overnight. The resultingmixture was cooled in an ice bath and the basic solution was neutralizedwith 2N citric acid until slightly acidic. The mixture was concentratedunder reduced pressure to remove the volatile materials, after whichtime the remaining aqueous phase was extracted with EtOAc (3×26 mL).These combined organic phases were dried over MgSO₄, filtered, andconcentrated under reduced pressure to give 2.26 g (146% of theory) ofpale yellowish white solid. This crude material was dissolved in a 10%MeOH/CH₂Cl₂ solution and adsorbed onto 30 g of silica. The adsorbedmaterial was divided and chromatographed on an ISCO normal phase columnover two runs, using a 40 g Redi-Sep column for both runs. The solventsystem was a gradient MeOH/CH₂Cl₂ system as follows: Initial 100%CH₂Cl₂, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min.The desired product eluted cleanly between 44-61 min. The desiredfractions were combined and concentrated under reduced pressure to yield1.74 g (113% of theory) of5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid, Cpd 9b, as a white solid.

D.5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}methyl)-2-methoxy-benzoicacid

A portion of Cpd 9b (0.27 g, 0.41 mmol) was dissolved in EtOAc (39mL)/THF (5 mL), filtered, and subsequently treated with gaseous HCl for15 min. After completion of the HCl addition, the reaction was slowlywarmed to room temperature and a solid precipitate formed. After 5 h thereaction appeared >97% complete by LC (@214 nm; 2.56 min.). The stirringwas continued over 3 d, then the solid was collected and rinsed with asmall amount of EtOAc. The resulting solid was dried under high vacuumunder refluxing toluene for 2.5 h to yield 0.19 g (71%) of desired Cpd9c as a white solid di-HCl salt.

Example 10

A. 4-{[1-(4-Phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acidmethyl ester

Using the procedure described for Example 3, substituting4-formyl-benzoic acid methyl ester for 3,4-dimethoxybenzaldehyde,4-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acidmethyl ester was prepared.

B.4-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoicacid methyl ester

4-{[1-(4-phenyl-1H-imidazol-2-yl)ethylamino]-methyl}-benzoic acid methylester was substituted for Cpd 1d of Example 1 and elaborated accordingto the procedure of Example 1 to prepare the product.

C.4-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoicacid

A solution of4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoicacid methyl ester (TFA salt), (0.043 g, 0.067 mmol) in 5 mL of THF wascooled in an ice bath. A cold (5-10° C.) 3M aqueous solution of LiOH (5mL) was added and the reaction mixture was stirred vigorously whilecold. Chilled (5-10° C.) 2M aqueous HCl (7.5 mL) was added dropwise toneutralize the mixture was stirred for 5 min, and then partiallyconcentrated in vacuo unheated. The resultant aqueous suspension wasextracted seven times with EtOAc. The extracts were dried over Na₂SO₄,filtered, and concentrated to afford 0.030 g of4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoicacid as a white powder. The material was taken up in EtOH and treatedwith 1M HCl in Et₂O. The solution was concentrated and the residue wastriturated with CH₃CN. A 0.021 g (53%) sample of4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoicacid was collected as its HCl salt. MS (ES⁺) (relative intensity): 513.2(100) (M+1).

Example 113-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzamide

A. 3-({[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzonitrile

Using the procedure described for Example 3, substituting3-formyl-benzonitrile for 3,4-dimethoxybenzaldehyde, the product wasprepared.

B.[1-{(3-Cyano-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester

3-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzonitrile wassubstituted for Cpd 1d of Example 1 and elaborated according to theprocedure of Example 1 to prepare the product.

C.[1-{(3-Carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester

A solution of[1-{(3-cyano-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester (0.070 g, 0.12 mmol) in 3 mL of EtOH was treatedwith 1.0 mL of 30% hydrogen peroxide followed immediately by 0.1 mL of a6M aqueous solution of NaOH. The reaction mixture was stirred vigorouslyfor 18 h and quenched by pouring into chilled (5-10° C.) water. Theaqueous solution was extracted five times with Et₂O and the combinedextracts were dried over MgSO₄, filtered, and concentrated to provide0.051 g of[1-{(3-carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester as a colorless residue (HPLC: 84% @ 254 nm and 77%@ 214 nm). MS (ES⁺) (relative intensity): 612.5 (100) (M+1). This samplewas of sufficient quality to use in the next reaction without furtherpurification.

D.3-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzamide

[1-{(3-carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester may be BOC-deprotected using the proceduredescribed in Example 1 for the conversion of Cpd 1e to Cpd 1f to providethe title compound.

Example 124-{2-Amino-2-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-3,5-dimethyl-benzamide

A. {1-[2-(2-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-ethyl}-carbamic acidtert-butyl ester

Compound 2a was prepared according to Example 1 using the appropriatereagents, starting materials and methods known to those skilled in theart.

B. {1-[4-(2-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-carbamic acidtert-butyl ester

Following the procedure described in Example 1 for the conversion ofCompound 1a to Compound 1b, and using the appropriate reagents andmethods known to those skilled in the art, Cpd 12b, was prepared.

C. 1-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-ethylamine

Using the procedure described for the conversion of Cpd 1e to 1f,Compound 12c was prepared.

D.[1-[{1-[4-(2-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester

Using the procedure described in Example 9, Step D, and substituting1-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-ethylamine for1-(4-phenyl-1H-imidazol-2-yl)-ethylamine, the product was prepared.

E.{2-(4-Carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamicacid tert-butyl ester

To a solution of[1-[{1-[4-(2-bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester (294 mg; 0.4 mmol) in DMF (2 mL) was added Zn(CN)₂(28 mg; 0.24 mmol). The resulting mixture was degassed with Argon for 5min, then Pd(PPh₃)₄ (92 mg; 0.08 mmol) was added neat, and the systemwas immediately warmed to 100° C. After heating for 6 h, the reactionwas cooled to rt and partitioned between EtOAc and water. The organicphase was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude material was subjected to reverse phase HPLC(water/acetonitrile/0.1% TFA). The fractions of interest were combined,basified with saturated aqueous NaHCO₃ and extracted twice with EtOAc.The EtOAc extracts were combined, dried over Na₂SO₄, filtered, andconcentrated to afford 146 mg (54%) of desired{2-(4-carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamicacid tert-butyl ester (HPLC: 96% @ 254 nm and 97% @ 214 nm). This samplewas of sufficient quality to use in the next reaction without furtherpurification.

F.4-{2-Amino-2-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-3,5-dimethyl-benzamide

{2-(4-carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamicacid tert-butyl ester may be BOC-deprotected using the proceduredescribed in Example 1 for the conversion of Cpd 1e to Cpd 1f to givethe title compound.

Example 133-(2-{1-[[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoicacid

A. 1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethylamine

Using the procedure described in Example 12, and the appropriatelysubstituted starting materials and reagents,1-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-ethylamine was prepared.

B.{1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-amine-

Using the procedure described in Example 3, and substituting1-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-ethylamine for1-(4-phenyl-1H-imidazol-2-yl)-ethylamine, the product was prepared.

C.[1-[{1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e,substituting{1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-aminefor Cpd 1d and substituting2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionicacid of Example 8 for2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionicacid, the product was prepared.

D.3-(2-{1-[[2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoicacid

To a solution of[1-[{1-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester (290 mg; 0.40 mmol) in DMF (5 mL) was added K₂CO₃(262 mg; 1.9 mmol) and the resulting mixture was degassed with Argon for5 min. At this time, Pd(OAc)₂ (8.9 mg; 0.04 mmol) and1,1-bis(diphenylphosphino) ferrocene (46 mg; 0.083 mmol) were added.Carbon monoxide was then bubbled through the resulting mixture for 10min at rt, the reaction was capped, and warmed to 100° C. for 6 h. Aftercooling to rt the mixture was partitioned between EtOAc and water,filtered through Celite, and then separated. The aqueous phase was thenwashed with a second portion of EtOAc. The aqueous phase was thenacidified to pH 5 with 2N citric acid and the resulting aqueous solutionextracted with EtOAc (4×). These latter EtOAc extracts were combined,dried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the crude product (HPLC: 87% at 254 nm).

E.3-(2-{1-[[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoicacid

3-(2-{1-[[2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoicacid may be BOC-deprotected using the procedure described in Example 1for the conversion of Cpd 1e to Cpd 1f to give the title compound.

Example 144-(2-Amino-2-{[2-hydroxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide

A. [2-Benzyloxy-1-(2-oxo-2-phenyl-ethylcarbamoyl-ethyl]carbamic acidtert butyl ester

The product was prepared using the procedure described in Example 1 andsubstituting N-α-BOC-L-serine benzyl ester for N-α-CBZ-L-alanine.

B. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]carbamic acid tertbutyl ester

By the procedure described in Example 1 for the conversion of Cpd 1a toCpd 1b, [2-benzyloxy-1-(2-oxo-2-phenyl-ethylcarbamoyl-ethyl]-carbamicacid tert butyl ester was converted to the product.

C. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethylamine

[2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-carbamic acid tertbutyl ester may be BOC-deprotected using the procedure described inExample 1 for the conversion of Cpd 1e to Cpd 1f to give the product.

D. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-isopropyl-amine

By the procedure described in Example 1 for the conversion of Cpd 1c toCpd 1d, [2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethylamine wasconverted to the product.

E.[1-{[2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e,substituting[2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-isopropyl-amine for Cpd1d and substituting2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionicacid of Example 8 for2-tert-butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionicacid, the product was prepared.

F.4-(2-Amino-2-{[2-hydroxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide(TFA salt)

A solution of[1-{[2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester, (0.287 g, 0.439 mmol), in chloroform (10 mL) wascooled in an ice bath and treated with 0.62 mL (4.4 mmol) ofiodotrimethylsilane. The reaction, which immediately clouded, was warmedslowly to room temperature while stirring. After 16 h, the reaction wascooled in an ice bath to 5-10° C. and treated with 100 mL of MeOH. Thequenched mixture was stirred at 5-10° C. for 30 min, removed from theice bath and stirred for an additional 30 min, and concentrated in vacuoto obtain 0.488 g of orange residue that was subjected to reverse phaseHPLC (water/acetonitrile/0.1% TFA). The fractions of interest werecombined and the sample was lyophilized to afford 0.150 g (59%) of4-(2-amino-2-{[2-hydroxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide(TFA salt) as a white powder (HPLC: 99% @ 254 nm and 100% @ 214 nm). MS(ES⁺) (relative intensity): 464.1 (100) (M+1).

Example 15(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid

A. Trifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester

To a cooled (0° C.) solution of 4-bromo-3,5-dimethylphenol (3.05 g, 15.2mmol) in pyridine (8 mL) was added trifluoromethanesulfonic anhydride(5.0 g, 17.7 mmol) dropwise. After completion of addition, the resultingmixture was stirred at 0° C. for 15 min, and then at rt overnight. Thereaction was quenched by addition of water, and then extracted withEtOAc. The organic extracts were washed sequentially with water, 2N HCl(2×), brine, and then dried over MgSO₄. Filtration and evaporation todryness afforded Compound 15b (5.30 g, 95%) as a colorless oil. ¹H NMR(300 MHz, CDCl₃): δ 2.45 (6H, s), 7.00 (2H, s).

B. 4-Bromo-3,5-dimethylbenzoic acid

To a solution of Compound 15b (6.57 g, 19.7 mmol) in DMF (65 mL) wereadded K₂CO₃ (13.1 g, 94.7 mmol), Pd(OAc)₂ (0.44 g, 1.97 mmol) and1,1′-bis(diphenylphosphino)ferrocene (2.29 g, 4.14 mmol). The resultingmixture was bubbled in gaseous CO for 10 min and was heated to 60° C.for 7.5 h with a CO_((g)) balloon. The cooled mixture was partitionedbetween aqueous NaHCO₃ and EtOAc, and filtered. The aqueous phase wasseparated, acidified with aqueous 6N HCl, extracted with EtOAc, andfinally dried over Na₂SO₄. Filtration and concentration of the filtrateresulted in the crude Compound 15c as a brown residue, which was used inthe next step without further purification.

C. 4-Bromo-3,5-dimethyl-benzamide

A suspension of Compound 15c in DCM (40 mL) was added SOCl₂ (3.1 mL, 42mmol) and the mixture was heated at reflux for 2 h. Upon removal of thesolvent by evaporation, the residue was dissolved in DCM (40 mL) andammonium hydroxide (28% NH₃ in water, 2.8 mL) was added. The mixture washeated at 50° C. for 2 h and concentrated. The residue was diluted withH₂O, extracted with EtOAc, and the organic portion was dried overNa₂SO₄. After filtration and evaporation, the residue was purified byflash column chramotagraphy (eluent: EtOAc) to give the Compound 15d(2.90 g, 65% for 2 steps) as an off-white solid. ¹H NMR (300 MHz,CD₃CN): δ 2.45 (6H, s), 5.94 (1H, br s), 6.71 (1H, br s), 7.57 (2H, s);MS (ES⁺) (relative intensity): 228.0 (100%) (M+1).

Method B:

A mixture of Compound 15b (3.33 g, 10 mmol), PdCl₂ (0.053 g, 0.3 mmol),hexamethyldisilazane (HMDS, 8.4 mL, 40 mmol), and dppp (0.12 g, 0.3mmol) was bubbled with a gaseous CO for 5 min and then stirred in a COballoon at 80° C. for 4 h. To the reaction mixture was added MeOH (5mL). The mixture was stirred for 10 min, diluted with 2NH₂SO₄ (200 mL),and then extracted with EtOAc. The EtOAc extract was washed withsaturated aqueous NaHCO₃, brine, and then dried over Na₂SO₄. Filtrationand evaporation of the resultant filtrate gave a residue, which waspurified by flash column chromatography (eluent: EtOAc) to give Compound15d (1.60 g, 70%) as a white solid.

D. 2-tert-Butoxycarbonylaminoacrylic acid methyl ester

To a suspension of N-Boc-serine methyl ester (Cpd 15e, 2.19 g, 10 mmol)and EDC (2.01 g, 10.5 mmol) in DCM (70 mL) was added CuCl (1.04 g, 10.5mmol). The reaction mixture was stirred at rt for 72 h. Upon removal ofthe solvent, the residue was diluted with EtOAc, washed sequentiallywith water and brine and then dried over MgSO₄. The crude product waspurified by flash column chromatography (eluent: EtOAc:hexane ˜1:4) togive Compound 15e (1.90 g, 94%) as a colorless oil. ¹H NMR (300 MHz,CDCl₃): δ 1.49 (9H, s), 3.83 (3H, s), 5.73 (1H, d, J=1.5 Hz), 6.16 (1H,s), 7.02 (1H, s).

E.(Z)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)acrylicacid methyl ester

A flask charged with Compound 15d (0.46 g, 2.0 mmol), Compound 15f (0.80g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol), DMF (8 mL) waspurged with N_(2 (g)) 3 times. After the addition oftris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA(0.31 mL, 2.2 mol), the reaction mixture was heated at 110° C. for 24 h.At that time, the reaction was quenched by addition of water, and thenextracted with EtOAc. The organic phase was washed with 1N HCl,saturated aqueous NaHCO₃, brine, and dried over MgSO₄. The mixture wasconcentrated to a residue, which was purified by flash columnchromatography (eluent: EtOAc:hexane ˜1:1 to EtOAc only) to giveCompound 15 g (0.40 g, 57%) as a white solid. ¹H NMR (300 MHz, CD₃OD): δ1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1H, s), 7.56 (2H, s);¹³C NMR (75 MHz, DMSO-d₆): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4,128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6; MS (ES⁺) (relativeintensity): 349.1 (38%)(M+1).

F.(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionicacid methyl ester

Into a reactor charged with a solution of Compound 15 g (0.56 g, 1.6mmol) in degassed MeOH (80 mL) was added [Rh(cod)(R,R-DIPAMP)]⁺BF₄ ⁻under a stream of argon. The reactor was sealed and flushed with H₂,stirred at 60° C. under 1000 psi of H₂ for 14 d. The crude product waspurified by flash column chromatography (eluent: EtOAc:hexane ˜1:1) toafford Compound 8c (0.54 g, 96%) as a white solid. ee: >99%; ¹H NMR (300MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65(3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, br s),6.09 (1H, br s), 7.46 (2H, s); MS (ES⁺) (relative intensity): 250.9(100) (M−Boc)⁺.

G.(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionicacid

Into an ice-cooled solution of Compound 8c (0.22 g, 0.63 mmol) in THF(3.5 mL) was added an aqueous LiOH solution (1N, 3.5 mL) and stirred at0° C. Upon completion of the reaction, the reaction was concentrated andthe aqueous phase was neutralized with cooled aqueous 1N HCl at 0° C.,and extracted with EtOAc. The combined extracts were dried over Na₂SO₄overnight. Filtration and evaporation of the filtrate to dryness led toCompound 8d (0.20 g, 94%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd,J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s),7.80 (1H, s); MS (ES⁺) (relative intensity): 236.9 (6) (M−Boc)⁺.

Example 16 Racemic2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid

A. Racemic2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionicacid methyl ester

To a reactor charged with a solution of Compound 15 g (0.68 g, 1.95mmol) in MeOH (80 mL) was added 10% Pd—C (0.5 g). The reactor wasconnected to a hydrogenator and shaken under 51 psi of H₂ overnight. Themixture was filtered through a pad of Celite and the filtrate wasconcentrated to dryness to give Compound 16a (0.676 g, 99%) as a whitesolid. The ¹H NMR spectrum was identical to that of(S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionicacid methyl ester, Compound 8c.

B. Racemic2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionicacid

Using the procedure described for Example 15, for the preparation of(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionicacid, racemic2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionicacid, Compound 16b, was prepared.

Using the procedures of the Examples above and the appropriate reagents,starting materials and purification methods known to those skilled inthe art, other compounds of the present invention may be preparedincluding but not limited to:

TABLE VI Mass Spectral Data for Selected Compounds Theoretical MeasuredCpd MW MW (MH⁺) 1 538 539 2 520 521 3 573 574 4 541 542 5 527 528 6 555556 7 569 570 8 593 594 9 553 554 10 603 604 11 589 590 12 587.2 588.313 589.3 590.2 14 569.3 570.2 15 500.2 499.2 16 475.3 476.1 17 583.28584.5 18 569.26 570.2 19 633.2 634.0 20 599.3 600.2 21 634.3 635.2 22634.3 635.2 23 598.3 599.2 24 580.3 581.1 25 471.26 472.4 26 633.2 634.027 580.3 581.1 28 598.3 599.2 29 599.3 600.0 30 680.3 681.2 31 512.2 51332 498.3 499.1 33 498.3 499.1 34 528.3 529.2 35 514.3 515.1 36 462.26463.4 37 482.23 483.4 38 446.27 447.5 39 450.26 451.5 40 530.3 531.2 41445.3 446.1 42 563.3 564.2 43 504.23 505.3 44 504.23 505.3 45 513.24514.3 46 492.27 493.2 47 479.25 480.1 48 512.2 513.2 49 540.2 541 50539.25 540.2 51 553.3 554.1 52 526.3 527.1 53 609.3 610.2 54 458.2 45955 458.2 459 56 474.3 475.2 57 469.25 470.1 58 543.2 544.3 59 513.3514.2 60 445.3 446.2 61 456.2 457.1 62 498.2 499.1 63 436.3 437.1 64601.3 602.2 65 422.1 423.1 66 463.3 464.5 67 491.3 492.1 68 436.3 437.169 463.3 464.1 70 454.2 455.0 71 456.2 457.0 72 498.2 499.1 73 463.3464.2 74 577.3 578.6 75 555.3 555.8 76 513.3 514.2 77 525.3 526.3 78497.3 498.3 79 525.3 526.2 80 512.2 513.2 81 484.2 485.4 82 438.24 439.283 486.24 487.5 84 438.24 439.0 85 463.3 464.2 86 433.2 434.2 87 522.2523 88 526.3 527.4 89 526.3 527.4 90 511.3 512.4 91 493.2 494.4 92 469.2470.2 93 469.2 470.4 94 495.3 496.2 95 495.3 496.2 96 498.3 499.2 97536.2 537.2 98 560.3 561.2 99 518.3 519.2 100 518.3 519.2 101 546.2547.2 102 528.3 529.2 103 536.2 537.2 104 510.3 511.2 105 544.3 545.3106 496.3 497.2 107 481.3 482.3 108 523.3 524.8 109 509.3 510.4 110509.3 510.3 111 509.3 510 112 509.3 510 113 495.3 496.4 114 495.3 496.1115 496.28 497.4 115 496.28 497.4 116 438.24 439.4 117 438.24 439.4 118436.2 437.3 119 394.2 395.2 120 525.3 526.2 121 539.3 540.3 122 521.3522.3 123 464 465 124 421 422 125 450.26 451.5 126 456.23 457.3 127487.3 488.5 128 487.3 488.6 129 422.2 423.3 130 450 451 131 422.2 423.3132 394.2 395.2 133 464.2 465.3 134 496.3 497.4 135 450.26 451.37 136495.3 496.4 137 447.3 448.4 138 526.3 527.4 139 653.4 654.5 140 462.3463.4 141 488.17 489.16 142 450.26 451.40 143 447.3 448.4 144 419.2420.3 145 496.28 497.32 146 426.21 427.39 147 454.21 455.22 148 477.3478 149 488.2 489 150 470.3 471 151 488.2 489 152 398.2 399 153 393 394154 392 393 155 454.21 455.21 156 470.27 471.36 157 477.2 478.4 158468.2 469.4 159 496.3 497.4 160 429.2 430.4 161 420.2 421.4 162 448.3449.4 163 438.24 439.1 164 556.23 557.1 165 434.27 435.1 166 420.25421.1 167 449.3 450.2 168 433.3 434.2 169 415.2 416.2 170 434.3 435.3171 392.2 393.3 172 497.2 498.3 173 479.2 480.3 174 434.3 435.3 175484.2 485.2 176 420.2 421.4 177 454.2 455.3 178 433.3 434.1 179 489.3490.1 180 489.3 489.9 181 447.3 448.1 182 447.3 448.3 183 433.3 434.2184 433.3 434.2 185 405.2 406.2 186 387.2 388.2 187 406.2 407.2 188378.2 379.2 189 427.2 428 190 446.3 447.4 191 418.2 419.4 192 418.2419.3 193 390.2 391.3 194 406.2 407.5 195 378.2 379.3 196 419.2 420.4197 433.3 434.1 198 350.2 351.1 199 378.2 379.2 202 391.2 392 203 391.2391.9 204 378.2 379 205 406.2 407 206 392.2 393.3 207 392.2 393.2 208378.2 379.3 209 378.2 379.2 210 364.2 365.2 211 364.2 365.2 212 350.2351.2 213 350.2 351.1 214 378.2 379.1 215 378.2 379.1 216 406.2 407.2217 406.2 407.1 218 468.3 469.4 219 440.2 441.3 220 468.3 469.4 221440.2 441.2 222 392.2 393.2 223 420.3 421.2 224 420.3 421.1 225 392.2393.2 226 539 540 227 539 540 228 587 588 229 633 634 230 599.3 599.8231 512.2 513.2 239 617.2 618.2 242 563.3 564.2 246 519.3 520.0 247548.3 549.2 248 552.2 553.2 249 536.2 537.0 250 526.3 527.2 251 512.3513.2 252 554.3 555.3 253 540.2 541.2 254 540.2 541.2 255 554.3 555.3256 529.2 530.2 257 543.2 543.9 260 542.2 543.2 261 514.2 515.1 262528.2 529.1 266 512.2 513.2 267 535.2 536.0 268 556.3 557.2 269 525.2526.0 270 511.2 512.2 271 539.2 540.2 272 525.2 526.0 273 541.2 542.4274 618.3 619.2 275 589.2 590.2 276 559.2 560.2 277 559.2 560.2 278617.2 618.2 279 528.2 528.9 280 583.3 584.4 281 555.2 556.2 282 569.3570.2 283 541.2 542.2 284 555.2 556.3 285 541.2 542.4 286 516.2 517.0287 502.2 503.1 288 648.6 648.0 289 695.2 695.7 290 648.6 648.0 291648.6 648.0 292 526.3 527.4 293 562.2 563.2 294 562.2 563.2 295 568.3569.3 296 638.3 638.8 297 513.2 513.7 298 583.3 583.8 299 612.3 613.3300 608.3 609.3 301 644.3 644.7 303 515.2 515.8 304 501.2 502.2 305617.3 617.8 306 661.3 661.8 307 566.3 566.8 308 661.3 661.8 309 649.3650.0 310 641.3 642.3 311 554.3 555.3 312 554.3 555.3 313 554.3 555.3314 554.3 555.3 315 627.3 628.3 316 540.2 541.3 317 540.2 541.3 318589.2 590.2

BIOLOGICAL EXAMPLES

Opioid receptor binding affinity of the compounds of the presentinvention was determined according to the following procedures and theindicated results were obtained.

Example 1 Rat Brain Delta Opioid Receptor Binding Assay

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) arekilled by cervical dislocation, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainsare separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains arehomogenized in Tris buffer in a Teflon® glass homogenizer. Thehomogenate is diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet isresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation is used for the delta opioid binding assays. Followingincubation with the delta selective peptide ligand ˜4 nM [³H]DPDPE at25° C. for 2.5 h in a 96-well plate with total volume of 1 mL, the platecontents are filtered through Wallac filtermat B sheets on a Tomtec96-well harvester. The filters are rinsed three times with 2 mL of 10 mMHEPES (pH 7.4), and dried in a microwave oven 2 min twice. To eachsample area 2×50 μL of Betaplate Scint scintillation fluid (LKB) isadded and analyzed on a LKB (Wallac) 1205 BetaPlate liquid scintillationcounter.

The data are used to calculate either the % inhibition compared tocontrol binding (when only a single concentration of test compound isevaluated) or a K_(i) value (when a range of concentrations is tested).% inhibition is calculated as: [(total dpm-test compound dpm)/(totaldpm-nonspecific dpm)]*100. Kd and Ki values were calculated usingGraphPad PRISM data analysis program. The biological activity of thecompounds of the present invention is shown in Table VII.

Example 1a Rat Brain Delta Opioid Receptor Binding Assay-Version 1a

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) werekilled by cervical dislocation, and their brains removed and placedimmediately in ice-cold Tris HCl buffer (50 mM, pH 7.4). The forebrainswere separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains werehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate was diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet wasresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation was used for the delta opioid binding assay. Followingincubation with 0.1 nM of the delta selective ligand [³H]naltrindole at25° C. for 2.5 h in a 96-well plate with total 1 mL, the plate contentswere filtered through Wallac filtermat B sheets on a Tomtec 96-wellharvester. The filters were rinsed three times with 2 mL of 10 mM HEPES(pH 7.4), and dried in a microwave oven. To each sample area, BetaplateScint scintillation fluid (LKB) was added and the resultingradioactivity quantified on a LKB (Wallac) 1205 BetaPlate liquidscintillation counter. Kd and Ki values were calculated using theGraphPad PRISM data analysis program. The biological activity of thecompounds of the present invention is shown in Table VII.

Example 2 Rat Brain Mu Opioid Receptor Binding Assay

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) arekilled by cervical dislocation, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainsare separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains arehomogenized in Tris buffer in a Teflon® glass homogenizer. Thehomogenate is diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet isresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation is used for the mu-opioid binding assays. Followingincubation with the mu selective peptide ligand .about. 0.8 nM [³H]DAMGOat 25° C. for 2.5 h in a 96-well plate with total 1 mL, the platecontents are filtered through Wallac filtermat B sheets on a Tomtec96-well harvester. The filters are rinsed three times with 2 mL of 10 mMHEPES (pH7.4), and dried in a microwave oven 2 min twice. To each samplearea 2×50 μL of Betaplate Scint scintillation fluid (LKB) is added andanalyzed on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.

The data are used to calculate either the % inhibition compared tocontrol binding (when only a single concentration of test compound isevaluated) or a K_(i) value (when a range of concentrations is tested).% inhibition is calculated as: [(total dpm-test compound dpm)/(totaldpm-nonspecific dpm)]*100. Kd and Ki values were calculated usingGraphPad PRISM data analysis program. The biological activity of thecompounds of the present invention is shown in Table VII.

Example 2a Rat Brain Mu Opioid Receptor Binding Assay-Version 2a

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) werekilled by cervical dislocation, and their brains removed and placedimmediately in ice-cold Tris HCl buffer (50 mM, pH 7.4). The forebrainswere separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains werehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate was diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet wasresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation was used for the mu opioid binding assay. Followingincubation with 0.8 nM of the mu selective ligand [³H]DAMGO at 25° C.for 2.5 h in a 96-well plate with total 1 mL, the plate contents werefiltered through Wallac filtermat B sheets on a Tomtec 96-wellharvester. The filters were rinsed three times with 2 mL of 10 mM HEPES(pH 7.4), and dried in a microwave oven. To each sample area, BetaplateScint scintillation fluid (LKB) was added and the resultingradioactivity quantified on a LKB (Wallac) 1205 BetaPlate liquidscintillation counter. Kd and Ki values were calculated using theGraphPad PRISM data analysis program.

TABLE VII r Ki δ * r Ki δ * Ver. 1a r Ki μ * Cpd (nM) (nM) (nM) 1 13.21.1 2 3 4 11, 17 2.41 5 630, 183 1.19 6 1.7 7 8 0.43, 0.15 0.51 9 0.110.16 10 11 0.54 0.23 12 0.08 13 14 0.36 15 16 17 60 0.22 18 0.38-14.40.75, 1.1 19 20 21 22 23 24 25 26 27 28 29 28 25 30 31 32 33 34 35 36 3738 39 40 41 42 43 44 45 46 47 48 0.24 0.14 49 50 0.58 1.68 51 52 53 5455 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 0.66 0.5176 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 12 0.26 115116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133134 135 136 137 138 139 140 141 142 143 144 145 146 147 149 150 151 152153 154 155 156 157 158 159 160 161 162 163 4.51 0.03 164 120 0.38 16523.6 0.07 166  5.58, 12.03 0.03, 0.07 167 10000 3.15 168 8867 5322 16910000 853 170 32.6 0.48 171 10000 141 172 10000 150 173 5069 45.7 174175 166 3.60 176 10000 156 177 255 13.4 178 104 0.6 179 10000 7116 1805221 1209 181 341 1.3 182 1859 7 183 604 4 184 10000 19.5 185 182 6716186 515 5314 187 5198 121 188 541 307 189 360 277 190 13.8 2.61 191727.3 189 192 7.64 0.09 193 182.1 21.1 194 14.8 0.06 195 306.2 9.29 196197 4.27 0.9 198 5178 152 199 26.3 0.3 202 31.5 5.9 203 49.3 29.1 204205 4.44 0.14 206 5.8 0.2 207 5.3, 5.37, 14.7 0.05, 0.08, 0.1 208 33 1.3209 708 17 210 1862 420.3 211 180 5.9 212 1278 103 213 5658 1263 214 30844 215 126 0.43 216 1.14 0.04 217 5.4 1.08 218 1.45 0.03 219 87.83 0.87220 6921 157.2 221 9.58 0.36 222 394 91.2 223 2.6 0.87 224 1.41 0.03 225112 0.73 226 48 227 0.08, 0.46 0.96 228 27.8 0.35 229 230 10 5 231 10706.19 239 0.1 0.44 242 0.18 0.59 246 0.035 0.15 247 0.4 0.61 248 0.440.11 249 0.18 0.12 250 0.21 0.06 249 0.18 0.12 250 0.21 0.06 251 0.260.08 249 0.18 0.12 250 0.21 0.06 251 0.26 0.08 256 3.82 7.08 257 14.01.22 260 0.13 0.24 261 8.01 0.79 262 17.5 1.1 266 267 0.46 1.53 268 2690.61 6.24 0.37 270 1.03 4.47 1.37 271 12.2 0.27 272 15.6 1.1 273 1140754 274 275 0.47 0.69 276 115 47 277 0.14 0.44 278 49 12 279 5.2 0.137280 32 3 281 721 399 282 907 185 283 6735 3572 284 1526 1033 285 28971868 286 0.11 0.05 287 0.14 0.13 288 0.17 0.43 288 0.17 0.43 289 0.1,3.8 0.25 290 0.69 0.43 291 0.12 0.47 292 100 0.65 293 3175 646 295 3.950.18 296 2.2 0.49 297 44 0.11 298 44 0.3 299 1.16 0.44 300 0.29 0.09 3010.76 0.09 303 24.5 3.87 304 119 161 305 1.24 0.2 306 0.18 0.9 307 0.070.4 308 0.48 1.2 318 1220 357 * The binding assays described above maybe associated with a margin of error between 10-20%.

Example 3 Human Mu Opioid Receptor Binding Assay

Membranes from Chinese Hamster Ovary cells expressing the human p opioidreceptor (Perkin Elmer #RBHOMM400UA) are homogenized in assay buffer (50mM Tris, pH 7.5 with 5 mM MgCl₂) using a glass tissue grinder, Teflonpestle and a Steadfast Stirrer (Fisher Scientific). The concentration ofmembranes is adjusted to 300 μg/mL in assay buffer and 100 μL isdispensed into each well of the assay plate, a 96 well round bottompolypropylene plate. Compounds to be tested are solubilized in DMSO(Pierce), 10 mM, then diluted in assay buffer to 6× the desired finalconcentration. The ligand, ³H-Damgo (Perkin Elmer #NET-902) is alsodiluted in assay buffer to 3.6 nM. In a second 96 well round bottompolypropylene plate, known as the premix plate, 60 μL of the 6× compoundis combined with 60 μL of 3.6 nM ³H-Damgo. From this premix plate 50 μLis transferred to the assay plate containing the membranes, induplicate. The assay plate is incubated for 2 h at room temperature. AGF/C 96 well filter plate (Perkin Elmer #6005174) is pretreated with0.3% polyethylenimine for 30 min. The contents of the assay plate arefiltered through the filter plate using a Packard Filtermate Harvester,and washed 3 times with 0.9% saline that is 4° C. The filter plate isdried, the underside sealed, and 30 μL Microscint20 (Packard #6013621)added to each well. A Topcount-NXT Microplate Scintillation Counter(Packard) is used to measure emitted energies in the range of 2.9 to 35KeV. Results are compared to maximum binding, wells receiving noinhibitors. Nonspecific binding is determined in the presence of 1 μMunlabelled Damgo (Tocris #1171). The biological activity of thecompounds of the present invention is shown in Table VIII.

The biological activity of the compounds of the present invention mayalso be measured in a human delta opioid receptor binding assay usingthe following example.

Example 4 Human Delta Opioid Receptor Binding Assay

This assay is designed to test the ability of a compound to interferewith the binding of tritiated Naltrindole to the human delta subtype 2opioid receptor. Membranes from Chinese Hamster Ovary cells expressingthe human delta subtype 2 opioid receptor (Perkin Elmer #RBHODM400UA)are homogenized in assay buffer (50 mM Tris, pH 7.5 with 5 mM MgCl₂)using a glass tissue grinder, Teflon pestle and a Steadfast Stirrer(Fisher Scientific). The concentration of membranes is adjusted to 100μg/mL in assay buffer and 100 μL is dispensed into each well of theassay plate, a 96 well round bottom polypropylene plate. Compounds to betested are solubilized in DMSO (Pierce), 10 mM, then diluted in assaybuffer to 6× the desired final concentration. The ligand, ³H-Naltrindole(Perkin Elmer #NET-1065) is also diluted in assay buffer to 6 nM. In asecond 96 well round bottom polypropylene plate, known as the premixplate, 60 μL of the 6× compound is combined with 60 μL of 6 nM³H-Naltrindole. From this premix plate 50 μL is transferred to the assayplate containing the membranes, in duplicate. The assay plate isincubated for 30 min at room temperature. A GF/C 96 well filter plate(Perkin Elmer #6005174) is pretreated with 0.3% polyethylenimine for 30min. The contents of the assay plate are filtered through the filterplate using a Packard Filtermate Harvester, and washed 3 times with 0.9%saline that is 4° C. The filter plate is dried, the underside sealed,and 30 μL Microscint20 (Packard #6013621) added to each well. ATopcount-NXT Microplate Scintillation Counter (Packard) is used tomeasure emitted energies in the range of 2.9 to 35 KeV. Results arecompared to maximum binding, wells receiving no inhibitors. Nonspecificbinding is determined in the presence of 1 μM unlabelled Naltrindole(Sigma #N115).

Biological activity measured for select compounds of the presentinvention are listed in Table VIII below, including δ- and μ-opioidreceptor binding (K_(i)), as determined using the procedures outlinedabove.

TABLE VIII hKi δ* hKi μ* Cpd (nM) (nM) 1 3.6 2 2.9 3 13 4 5.5 5 3.9 6 27 6.8 8 2.5, 4.4 9 10.9 10 15.5 11 5.1 12 4.1 13 4.8 14 4.7 15 285 16 1617 2.2 18 1.7 19 18.2 20 63 21 37.6 22 ~200 23 34.3 24 9.3 26 17 27 3028 44 29 38 30 34 31 19 32 6.8 33 6.9 34 19 35 2.8 36 5.6 37 183 38 1939 0.9 40 152 41 1.6 42 5.8 43 6.9 44 8.7 45 1.2 46 35 47 22 48 0.4 4948 50 1.4 51 113 2.7 52 66 12.1 53 96 13.1 54 172 1.1 55 44 1.8 56 22565.3 57 2.2 0.66 58 70 8.5 59 120 5.1 60 114 2 61 243 3 62 69 2.4 63 47358 64 1108 117 65 517 0.36 66 550 6.5 67 438 4.5 68 59 0.6 69 272 4.4 7085 2.6 71 102 0.57 72 71 1.03 73 151 1.9 74 63 9.8 75 8.5 2.6 76 43.11.6 77 13.5 1.8 78 28.9 2.4 79 11.5 1.7 80 0.95 1.09 81 15.7 1.7 82 462.39 83 48 4.67 84 9.6 1.1 85 1175 5.4 86 400 1 87 38.9 12.6 88 16.2 5.889 19.3 9.2 90 6.6 0.7 91 15 4.8 92 5.4 0.25 93 9.5 0.9 94 403 4.1 95278 7.8 96 14.6 9.7 97 6.3 19.2 98 54 48 99 19.3 16 100 88 20 101 47 24102 5.2 3.5 103 9.7 23 104 484 100 105 742 410 106 279 150 107 584 2.95108 43.3 23.5 109 77 8.2 110 1402 191 111 307 6.4 112 135 9.5 113 16 11449 1.39 115 321 68 116 30.3 0.54 117 118 0.24 118 316, 1.04 212119 >10,000 185 120 740 20.8 121 182 25.3 122 107 12.8 123 84 47 1241279 1.7 125 237 8.6 126 164 7.8 127 710 47 128 58 129 25.3 130 712 1.6131 675 3.1 132 166 133 108 11.5 134 463 121 135 1040 7 136 1607 726 137445 138 1183 104 139 1263 58 140 985 79 141 252 52 142 454 8.2 143 691.6 144 251 1.3 145 267 146 71 147 241 149 408 150 992 151 1295152 >10,000 153 >10,000 154 >10,000 1 155 345 156 380 0.59 157 >10,0002.2 158 >10,000 0.23 159 400 8.6 160 >10000 >1000 161 >10000 >1000 162173 7.6 163 301, 63 0.67 164 16.3 165 322 0.45 166 300, 0.39, 0.5 375167 4.2 190 285 191 >10,000 192 0.62 193 >10,000 194 103 0.13195 >10,000 9.8 196 197 198 >10,000 140 199 209 0.29 203 501 13.7 2047.7 205 206 275.4 207 132.2 208 1.2 209 23 210 0.29 211 212 55 213 >1000214 29 215 1.5 216 217 506 218 189 3.92 219 16.2 220 377 221 0.42 222185 223 224 81.3 0.65 225 1.4 226 7.91 227 1.92 228 15.9 229 12 231 28239 242 2.35 246 5.63 256 2 257 3.4 260 0.58 261 2.58, 1.3 262 3.24 26669 267 6.88 268 5.79 269 21.5 270 3.27 271 15.5 272 1.93 273 325274 >1000 289 2.2 303 3.8 304 41

Example 5 Delta Opioid Receptor Functional Assay: [³⁵S]GTPγS BindingAssay in CHO-hδ Cell Membranes, Version 1

Preparation of Membranes

CHO-hδ cell membranes were purchased from Receptor Biology, Inc.(Baltimore, Md.). 10 mg/ml of membrane protein suspended in 10 mMTRIS-HC pH 7.2, 2 mM EDTA, 10% sucrose.

Membranes were maintained at 4-8° C. A portion (1 ml) of membranes wasadded into 15 mL cold binding assay buffer. The assay buffer contained50 mM HEPES, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EDTA.The membrane suspension was homogenized with a Polytron for 2 times andcentrifuged at 3000 rpm for 10 min. The supernent was then centrifugedat 18,000 rpm for 20 min. The pellet was saved in a tube and 10 ml assaybuffer was added into the tube. The pellet and buffer were mixed with aPolytron.

Incubation Procedure

The pellet membranes (20 μg/ml) were preincubated with SPA (10 mg/ml) at25° C. for 45 min in the assay buffer. The SPA (5 mg/ml) coupled withmembranes (10 μg/ml) was then incubated with 0.5 nM [³⁵S]GTPγS in thesame HEPES buffer containing 50 μM GDP in total volume of 200 μl.Increasing concentrations of receptor agonists were used to stimulate[³⁵S]GTPγS binding. The basal binding was tested in the absent agonistsand no specific binding was tested in the present 10 μM unlabeled GTPγS.The data were analyzed on a Top counter.

DataThe % of Basal=(stimulate−non specific)*100/(basal−non specific).EC50 values were calculated using a Prism program.

Example 6 Delta Opioid Receptor Functional Assay: [³⁵S]GTPγS BindingAssay in NG108-15 Cell Membranes, Version 2 Preparation of Membranes

NG108-15 cell membranes were purchased from Applied Cell Sciences(Rockville, Md.). 8 mg/ml of membrane protein suspended in 10 mM TRIS-HCpH 7.2, 2 mM EDTA, 10% sucrose.

Membranes were maintained at 4-8° C. A portion (1 ml) of membranes wasadded into 10 ml cold binding assay buffer. The assay buffer contained50 mM Tris, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EGTA. Themembrane suspension was homogenized with a Polytron for 2 times andcentrifuged at 3000 rpm for 10 min. The supernent was then centrifugedat 18,000 rpm for 20 min. The pellet was saved in a tube and 10 ml assaybuffer was added into the tube. The pellet and buffer were mixed with aPolytron.

Incubation Procedure

The pellet membranes (75 μg/ml) were preincubated with SPA (10 mg/ml) at25° C. for 45 min in the assay buffer. The SPA (5 mg/ml) coupled withmembranes (37.5 μg/ml) was then incubated with 0.1 nM [³⁵S] GTPγS in thesame Tris buffer containing 100 μM GDP in total volume of 200 μl.Increasing concentrations of receptor agonists were used to stimulate[³⁵S] GTPγS binding. The basal binding was tested in the absent agonistsand no specific binding was tested in the present 10 μM unlabeled GTPγS.The data were analyzed on a Top counter.

Data Analysis

The following parameters were calculated:

$\mspace{20mu}{{\%\mspace{14mu}{Stimulation}} = {\frac{\left( {{{test}\mspace{14mu}{compound}\mspace{14mu}{cpm}} - {{non}\text{-}{specific}\mspace{14mu}{cpm}}} \right)}{\left( {{{Basal}\mspace{14mu}{cpm}} - {{non}\text{-}{specific}\mspace{14mu}{cpm}}} \right).} \times 100}}$%  Inhibition = (%  stimulation  by  1  µM  SNC 80 − %  stimulation  by  1  µM  SNC 80  in  presence  of  test  compound) × 100/(%  Stimulation  by  1  µM  SNC 80 − 100)%  of  Basal = (stimulate − non  specific)^(*)100/(basal − non  specific).  EC₅₀  values  were  calculated  using  GraphPad  Prism.

Example 7 Mu Opioid Receptor Functional Assay: [³⁵S]GTPγS Binding Assaysin CHO-hMOR cell membranes, Versions 1 and 2

CHO-hMOR cell membranes were purchased from Receptor Biology, Inc.(Baltimore, Md.). About 10 mg/ml of membrane protein was suspended in 10mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose, and the suspension kept onice. One ml of membranes was added to 15 ml cold binding assay buffercontaining 50 mM HEPES, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1mM EDTA. The membrane suspension was homogenized with a Polytron andcentrifuged at 3,000 rpm for 10 min. The supernatant was thencentrifuged at 18,000 rpm for 20 min. The pellet was resuspended in 10ml assay buffer with a Polytron.

The membranes were preincubated with wheat germ agglutinin coated SPAbeads (Amersham) at 25° C. for 45 min in the assay buffer. The SPA bead(5 mg/ml) coupled membranes (10 μg/ml) were then incubated with 0.5 nM[³⁵S]GTPγS in the assay buffer. The basal binding is that taking placein the absence of added test compound; this unmodulated binding isconsidered as 100%, with agonist stimulated binding rising to levelssignificantly above this value. A range of concentrations of receptoragonists was used to stimulate [³⁵S]GTPγS binding. Both basal andnon-specific binding was tested in the absence of agonist; non-specificbinding determination included 10 μM unlabeled GTPγS.

Compounds were tested for function as antagonists by evaluating theirpotential to inhibit agonist-stimulated GTPγS binding. Radioactivity wasquantified on a Packard TopCount. The following parameters werecalculated:

$\mspace{20mu}{{\%\mspace{14mu}{Stimulation}} = {\frac{\left( {{{test}\mspace{14mu}{compound}\mspace{14mu}{cpm}} - {{non}\text{-}{specific}\mspace{14mu}{cpm}}} \right)}{\left( {{{Basal}\mspace{14mu}{cpm}} - {{non}\text{-}{specific}\mspace{14mu}{cpm}}} \right).} \times 100}}$%  Inhibition = (%  stimulation  by  1  µM  SNC 80 − %  stimulation  by  1  µM  SNC 80  in  presence  of  test  compound) × 100/(%  Stimulation  by  1  µM  SNC 80 − 100)EC₅₀ values were calculated using GraphPad Prism.

Biological activity measured for select compounds of the presentinvention are listed in Table VIII below, including δ- and μ-opioidreceptor functional data (% I and EC50), as determined from a single setof experiments using the procedures outlined above.

TABLE IX DOR GTP- DOR GTP- DOR GTP- MOR GTP MOR GTP MOR GTP bindingbinding binding binding binding MOR GTP binding Cpd Assay_v1Assay_v2_(—) Assay v2 assay v2 assay_v2 assay_v1% assay_v1 No. EC50 (nM)EC50 (nM) (% I) EC50 (nM) (% I) of Basal (% I) 1 88 22.10 4 46 66.125 >10,000 47.12 71 7.87 8 >10,000 94.03 1.2 13.95 9 3.4 67.13 14 0.659.70 17 1.3 68.64 2.5 8.71 18 >10,000 100 18 1.0 7.54 20 >10,000 78.7429 >10,000 79.05 48 >10,000 108.36 2.2 24.53 50 1.4 60.27 51 27 66.04 751.4 65.35 114 35 717.59 13.20 117 37 816.16 3.31 122 278.08 41.93 130 16866.39 1.62 131 99 391.98 28.64 146 27 740.77 2.79 147 51 779.35 1.00149 44 753.53 1.00 150 49 476.63 53.35 151 350 606.38 24.19 155 150655.93 14.32 163 21 1286.00 1.00 164 2500 1077.00 1.00 165 231 1182.001.00 166 21 1448.00 1.00 166 71 1425.00 1.00 167 780.00 17.00 170 1151031.00 26.00 173 147.00 85.00 174 20 864.00 42.00 175 471.00 53.00 177625.00 23.00 178 1059.00 10.00 181 1304.00 1.00 182 1091.00 6.00 1832320 962.00 27.00 184 862.00 13.00 190 3830 109, 194 70.00 192 76 383.0030.00 193 182.00 54.00 194 189 558.00 1.00 195 378.00 34.00 196 24620.00 1.00 197 140 582.00 1.00 199 217 465.00 11.00 202 1580 529.001.00 203 515 331.00 20.00 205 32 566.00 1.00 206 37 446.00 1.00 207 8.65 432, 1160 40.00 207 12 1183.00 21.00 208 475.00 1.00 209 295.00 10.00210 414.00 10.00 211 371.00 10.00 214 26000 295.00 3.00 215 1060 606.001.00 216 16 666.00 1.00 217 82 599.00 1.00 218 20 599.00 1.00 219 3560611.00 1.00 221 308 427.00 13.00 223 56 495.00 1.00 224 103 694.00 1.00225 2190 657.00 1.00 226 >10,000 19.71 227 >10,000 66.56 60.8 36.00 23048.93 239 >10,000 242 >10,000 91.45 246 0.3 47.01 4.5 21.30 247 44 41.89248 15 31.72 249 8 20.14 250 10 34.93 251 18 53.94 252 32.1 66.00 4.1524.00 253 1.35 52.00 251 28.00 254 6.27 62.00 316 42.00 255 13.1 54.003.48 33.00 256 >10,000 89.19 13 29.40 257 7.4 48.88 3.9 10.96260 >10,000 100.97 1.5 2.89 261 21 30.04 17 5.88 267 6 31.76 269 8621.18 48 1.00 270 1000 63.51 56 6.61 275 3 72.08 286 2.6 34.65287 >10,000 84.50 288 >10,000 74.54 289 >10,000 86.27 290 >10,000 52.41291 >10,000 96.52 295 2.2 71.66 1.4 8.21 296 7.9 69.41 2.2 9.35 299 2.31.0 12.11 300 32 2.6 15.40 301 >10,000 109.56 2.6 76.20 303 95 23.85 301.00 309 23.0 47.00 310 3920 51.00 311 1.02 41.00 312 58.7 35.00 3135.03 49 50.6 29.00 316 24.1 76

Example 8 In Vivo Assay-Stress-Induced Fecal Output (Fecal Output for 1hr)

This assay evaluates the fecal output in novel environment-stressed miceto that of acclimated controls.

Methods: Adult, male, Crl:CD-1 (ICR) mice, weighing ˜30-35 g were usedin these studies, with a minimum of 10 mice per dose group. One group ofmice was assigned as acclimated, or “non-stressed” controls. Thesecontrol mice were transported from colony housing, where they werehoused 3/cage in polycarbonate cages with access to food and water adlib. to the procedure room. The mice were removed from their home cagesand individually housed in 20 cm wide×20 cm deep×15 cm tall cages,equipped with a wire mesh bottom where they remained for a 16-18 hrperiod of acclimation to their novel environment. Mice were allowedaccess to food and water ad lib. during acclimation. The other groups ofmice were assigned as non-acclimated, or “stressed” treatment groups.Each mouse in each group was weighed and vehicle, or test compound, wasintragastrically administered by oral intubation in 0.5%methylcellulose. Mice were allowed access to water only ad lib. duringthe test period. After compound administrations, acclimated (control) aswell as non-acclimated (stressed) mice were individually housed in a 20cm wide×20 cm deep×15 cm tall cage, with a wire mesh bottom. Anabsorbant cardboard is placed beneath the cages. The number of fecalpellets excreted by each mouse was determined at hourly intervalsfollowing placement of the mice in the individual cages. Raw Data=# offecal pellets/mouse/hr. The mean fecal pellet output for each test groupwas calculated and the results expressed as a percent of the mean fecalpellet output of the control group (the acclimated, non-stressed group,to which vehicle only was administered). ANOVA was performed and Tukey'sMultiple Comparison Test used to compare the means, which wereconsidered significantly different when P<0.05. Data is shown in TableX, XI, and XII.

TABLE X Cpd dose Fecal Output (# pellets) NES % cpd % cpd % No. (mg/kg)control NES cpd Ctrl control NES 18 30 2.3 3.8 3.1 166.7 137.8 82.7 5030 2.3 7.0 3.3 304.3 143.5 47.1 55 30 3.9 14.1 8.3 361.5 212.8 58.9 5730 3.9 14.1 7.6 361.5 194.9 53.9 58 30 2.3 7.0 3.9 304.3 169.6 55.7 7530 3.1 9.1 6.4 293.5 206.5 70.3 75 30 1.9 3.9 1.4 206.7 73.3 35.5 78 303.6 7.3 3.3 202.8 91.7 45.2 79 30 3.6 7.3 7.1 202.8 197.2 97.3 80 30 3.67.3 5.5 202.8 152.8 75.3 80 30 3.9 13.1 10.3 335.9 264.1 78.6 85 30 5.412.0 7.9 222.2 146.3 65.8 87 30 7.3 12.9 10.3 176.7 141.1 79.8 89 30 5.011.6 6.4 232.0 128.0 55.2 90 30 3.1 12.9 10.3 416.1 332.3 79.8 91 30 3.112.9 8.9 416.1 287.1 69.0 92 30 3.6 11.1 9.2 308.3 255.6 82.9 93 30 3.611.1 5.0 308.3 138.9 45.0 94 30 2.7 9.1 9.4 337.0 348.1 103.3 95 30 2.79.1 8.5 337.0 314.8 93.4 97 30 7.3 12.9 4.8 176.7 65.8 37.2 102 30 5.715.0 3.4 263.2 59.6 22.7 103 30 7.3 12.9 10.2 176.7 139.7 79.1 107 305.7 15.0 13.1 263.2 229.8 87.3 111 30 7.2 10.3 4.4 143.1 60.8 42.5 11230 7.2 10.3 7.2 143.1 100.0 69.9 114 30 7.2 10.3 7.8 143.1 108.3 75.7118 30 5.4 12.0 7.2 222.2 133.7 60.2 133 30 5.5 12.1 9.9 220.0 180.081.8 143 10 3.7 13.6 9.1 367.6 245.9 66.9 143 30 7.5 9.2 5.2 122.7 69.356.5 144 30 3.7 13.6 11.5 367.6 310.8 84.6 178 30 3.2 8.8 5.5 275.0171.9 62.5 192 10 5.4 12.5 10.5 231.5 194.4 84.0 194 10 5.4 12.5 11.8231.5 218.5 94.4 194 30 8.1 11.0 4.2 135.8 51.9 38.2 194 30 3.1 4.8 4.9154.3 157.5 102.1 194 30 3.7 14.0 6.2 378.4 167.6 44.3 196 10 3.7 14.09.2 378.4 248.6 65.7 196 30 1.1 9.5 4.3 863.6 390.9 45.3 199 10 2.7 10.59.1 388.9 337.0 86.7 199 10 3.8 13.1 10.8 344.7 284.2 82.4 205 30 3.39.5 2.3 287.9 70.7 24.6 206 10 3.8 13.1 8.6 344.7 226.3 65.6 207 10 5.69.4 8.3 167.9 148.2 88.3 207 10 7.7 13.0 5.0 168.8 64.9 38.5 207 10 5.712.8 6.6 225.9 116.5 51.6 207 10 2.9 12.8 5.3 441.4 182.8 41.4 207 303.5 3.2 91.4 207 30 3.5 13.0 6.4 371.4 184.1 49.6 216 10 3.6 10.3 4.9286.1 136.1 47.6 218 30 2.7 10.5 3.7 388.9 137.6 35.4 223 30 3.1 4.8 5.0154.3 160.7 104.2 224 10 3.6 6.9 3.5 191.7 97.2 50.7 225 30 3.1 4.8 7.3154.3 234.7 152.1

TABLE XI Dose-dependent Mouse Fecal Pellet Output Test Cpd # of pelletsNES Compound (mg) No. control NES (% Ctrl) 0.3 0.5 1.0 3.0 5.0 6.0 10.030.0 75 235.7 93 2.7 8.3 307.4 6.2 5.5 3.2 97 6.1 11.6 190.2 14 7.5 3.597 4.8 10.1 210.4 9.1 10.4 2.3 102 5.3 10.7 201.9 6.9 4.5 2.22 114 3.410 294.1 9.6 7.7 5.4 200 3.556 8.8 247.5 8.1 8.2 5.8 207 5.2 11.4 219.211.4 12 4.9 207 4.8 8.6 179.2 9.4 8.6 6.7 207 3.4 10.8 317.6 7.5 5.5 3.5207 3.6 6.5 180.6 7.3 4.8 3.4 224 2.2 9.6 436.4 7.6 7.2 4.2

TABLE XII Dose-dependent Mouse Fecal Pellet Output Test: ComputedResults Cpd Compound (% control) Compound (% NES) No. 0.3 0.5 1.0 3.05.0 6.0 10.0 30.0 0.3 0.5 1.0 3.0 5.0 6.0 10.0 30 75 223.8 188.1 100 93229.6 203.7 119 74.7 66.27 38.55 97 226.2 123.0 57 119 64.66 30.17 97189.6 216.7 48 90.1 103 22.77 102 130.2 84.9 42 64.5 42.06 20.77 114282.4 226.5 159 96 77 54 200 227.8 230.6 163 92.05 93.18 65.91 207 219.2228.8 94.2 100 104.4 42.98 207 195.8 179.2 139.6 109 100 77.91 207 220.6161.8 103 69.44 50.93 32.41 207 202.8 133.3 94 112.3 73.85 52.31 224345.5 327.3 190.9 79.17 75 43.75

Example 9 In Vivo Assay: Stress-Induced Entire GI Tract Transit (6 HourTransit Time Test)

Methods: The animals used in these studies are male CD-1 mice, ave. wt.˜30 g. Procedure: Mice were housed in LAM under 12 h/12 h light/darkcycle, food & water ad lib. On the day before the experiments, the miceassigned to the “acclimated” (non-stressed) control group were placedinto individual wire mesh-bottomed cages, provided food and water adlib. The acclimated control group was in this new environment for 16-18hrs prior to beginning the test. On the day of the experiment, miceassigned to experimental groups were housed in home cages weretransported to procedure room and remain in their home cages until thestart of the transit portion of the study. Mice were intragastricallydosed with compounds (volume remains constant at 0.1 mL/10 g body wt) byoral gavage 30 minutes before carmine (a red vital dye that does nothave the drug-adsorbing properties of charcoal) is administered (0.25mL, 6% carmine in 0.5% methylcellulose). After the carmine marker wasadministered each mouse was placed in the novel environment cage. Onehour after administration of carmine, the fecal pellet output of eachanimal was recorded. At one-hour intervals thereafter the fecal pelletswere examined for the presence of carmine-dye. The number of mice thatexcreted a carmine-containing fecal pellet at the end of each hour postcarmine administration was recorded, until all mice had excreted carminein a fecal pellet or the end of 6 hrs post carmine administration,whichever occurred first. A variant of this novel environment stress(NES) paradigm is to use the same procedures of dye and compoundadministrations, but to use restraint (confinement in a small plastictube for 3 hr) as a stressor (RS=restraint stress), followed by twohours in an individual cage (total of 5 hr fecal transit time). Data isshown in Table XIII. The original data are quantal, i.e. a mouse in thetreatment group either did, or did not exhibit entire GI tract transit(excrete colored feces). The mouse entire GI tract (MEGIT) transit testcan thus be done in mice that are all acclimated (non-stressed), inwhich case the data are expressed as % control (vehicle only), or inmice that are exposed to NES or RS, in which cases the data areexpressed as % of the vehicle treated NES or RS group. Data is shown inTable XIII.

TABLE XIII Mouse entire GI tract transit test (MEGIT or MEGIT-NES orMEGIT-RS* MEGIT-NES MEGIT MEGIT-RS Entire GI transit entire GI entireCpd dose 6 hr transit 6 hr % GI transit 5 hr No. (mg) route (% NES) ctrl(% RS) 4 20 p.o. 100 18 30 p.o. 80 75 30 p.o. 125 75 60 p.o. 0 75 100p.o. 0 227 20 p.o. 100 242 20 p.o. 100 261 20 p.o. 103.6 270 20 p.o.112.5 289 20 p.o. 14.1 *RS = restraint stress; NES = novel environmentstress

Example 10 In Vivo Assay: Upper GI Tract Transit

Methods: The animals used in these studies were male CD-1 mice, ave. wt.˜30 g. Mice were housed under 12 h/12 h light/dark cycle, food & waterad lib. On the day of the experiment mice were assigned to experimentalgroups, including one vehicle-only group (=control). At 30 min beforeadministration of carmine dye, animals were dosed with vehicle orvehicle-plus-compound, mice were returned to their home cages after drugadministration. After administration of carmine, the animals were eitherreturned to their home cages (non-stressed) or individually placed inthe same metal cages as used in the fecal output or entire GI tracttransit to induce a novel environment stress. One hour afteradministration of carmine, mice were sacrificed by cervical dislocation,the abdomen opened midventrally, the small intestine from pylorus tocecum was removed, the mesentery divided in order to lay the intestinestraight & flat—without stretching. The total length of intestine andthe length of carmine-dyed intestine were measured in order to determinethe percent of the upper GI tract over which transit had occurred asfollows: {(Length of carmine-dyed intestine)/(Total length ofintestine)}×100=% upper GI transit. The data expressed were groupmeans±SD (or s.e.m.) and data expressed as % of control. Statistics:ANOVA with the Tukey-Kramer post-hoc test and means were consideredsignificantly different when P<0.05. Data is presented in Table XIV.

TABLE XIV Mouse Upper GI Transit Test (MUGIT) dose upper GI transit CpdNo. (mg) route (% ctrl) 8 30 p.o. 77.3 17 30 p.o. 37.3 18 10 p.o. 99.618 50 p.o. 69.9 18 5 p.o. 94.2 18 25 p.o. 83.0 18 100 p.o. 41.2 18 30p.o. 37.5 18 30 p.o. 53.1 48 30 p.o. 102.1 75 30 p.o. 71.1 75 60 p.o.56.0 75 100 p.o. 45.6 227 30 p.o. 93.9 256 30 p.o. 89.7 261 30 p.o. 87.7270 30 p.o. 96.5 287 30 p.o. 66.4 289 30 p.o. 76.4 315 30 p.o. 94.5

Example 11 Visceral Hyperalgesia Testing

Method: Rats were chronically instrumented with EMG electrodes in themuscles of the anterior abdominal wall. Distention of an intracolonicballoon, using a barostat apparatus, evoked increases in the EMGrecordings that are related to the pressure. Control responses arecompared with repeat stimulation 4 hours after zymosan is administeredto the colon (FIG. 1). Animals with 10% higher visceromotor responsesfor at least two distending pressures are considered to exhibit visceralhyperalgesia.

Compound 18 in 5 rats at repeated distentions of 40 mmHg administered at30 mg/kg, i.p., blocked the hyperalgesic response to colorectal balloondistention following zymosan (FIG. 2 and FIG. 3).

The agonistic or antagonistic activity of the compounds of the inventionat the kappa opioid receptor can be determined by known methods, forexample, by the procedure described in S. Giuliani, A. Lecci, M.Tramontana, C. A. Maggi, Role of kappa opioid receptors in modulatingcholinergic twitches in the circular muscle of guinea-pig colon. Brit JPharmacol 119, 985-9 (November, 1996).

What is claimed:
 1. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1 having the structure:


3. The compound of claim 2, having the structure:


4. The compound of claim 2, having the structure:


5. The compound of claim 2, having the structure:


6. A pharmaceutically acceptable salt of the compound according toclaim
 1. 7. The compound of claim 6, wherein the salt is a hydrochloric,hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic, or trifluoroacetic acid salt.
 8. The compound ofclaim 6, wherein the salt is a benzathine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium,lithium, magnesium, potassium, sodium, or zinc salt.